Perhydroisoindole derivatives and pharmaceutical compositions containing them

ABSTRACT

This invention relates to derivatives of perhydroisoindol of formula: ##STR1## in which the radicals R are hydrogen atoms or together form a bond, the symbols R&#39; are phenyl radicals which can be substituted by a halogen atom or a methyl radical in position 2 or 3, X is an oxygen atom or an NH radical, R 1  is optionally substituted phenyl, or cyclohexadienyl, naphthyl, or heterocyclyl, R 2  is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino, R 3  is halogen or OH and R 4  is H or halogen if R 3  is halogen, in their isomer forms, or mixture thereof, and possibly also their salts when they exist, and preparation thereof. The derivatives of the invention are particularly interesting as P substance antagonist.

This application is a National Stage Application of PCT/FR92/00429,filed May 15, 1992, now WO 92/20653, published Nov. 26, 1992.

FIELD OF THE INVENTION

The present invention relates to new perhydroisoindole derivatives ofthe general formula: ##STR2## and their salts when these exist, whichantogonise the effects of the substance P and are as a resultparticularly useful in the therapeutic sectors where this substance isknown to play a role.

BACKGROUND OF THE INVENTION

Products derived from the isoindole of the general formula: ##STR3##which exhibit opium activity, had been described in U.S. Pat. No.4,042,707.

These products exhibit no activity towards substance P.

In spite of the research carried out and in spite of the interestcreated [M. R. Hanley, TINS, (5) 139 (1982)], practically no product hadbeen discovered so far which acts specifically on substance P and whichhas a nonpeptide structure; accordingly, the isoindole derivatives ofgeneral formula (I) are of great interest.

DESCRIPTION OF THE INVENTION

In the general formula (I):

the R radicals are identical and represent hydrogen atoms or togetherform a bond,

the symbols R' are identical and they represent phenyl radicals whichare optionally substituted in position 2 or 3 by a halogen atom or by amethyl radical,

the symbol X represents an oxygen atom or an NH radical,

the symbol R₁ represents a phenyl radical which is optionallysubstituted by one or more halogen atoms or hydroxyl or alkyl radicalswhich may be optionally substituted (by halogen atoms or amino,alkylamino or dialkylamino radicals) alkoxy or alkylthio radicals whichmay be optionally substituted [by hydroxyl, amino, alkylamino ordialkylamino radicals optionally substituted (by phenyl, hydroxyl oramino radicals) or by dialkylamino radicals whose alkyl parts form withthe nitrogen atom to which they are attached, a heterocycle with 5 to 6members which may contain another heteroatom chosen from oxygen, sulphuror nitrogen, optionally substituted by an alkyl, hydroxyl orhydroxyalkyl radical)], or which is substituted by amino, alkylamino ordialkylamino radicals whose alkyl parts may form with the nitrogen atomto which they are attached, a heterocycle as defined above, orrepresents a cyclohexadienyl, naphthyl or a saturated or unsaturated,mono- or polycyclic heterocyclic radical containing 5 to 9 carbon atomsand one or more heteroatoms chosen from oxygen, nitrogen or sulphur,

the symbol R₂ represents a hydrogen or halogen atom or a hydroxyl,alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy,alkylthio, acyloxy, carboxyl, alkoxycarbonyl,dialkylaminoalkoxycarbonyl, benzyloxycarbonyl, amino, acylamino oralkoxycarbonylamino radical,

the symbol R₃ represents a halogen atom or a hydroxyl radical, and

the symbol R4 represents a hydrogen atom or, together with R₃,represents a halogen atom.

It is understood that the abovementioned alkyl or acyl radicals contain1 to 4 carbon atoms in a linear or branched chain.

When R' carries a halogen substituent, the latter may be chosen fromchlorine or fluorine.

When R₁ contains a halogen atom, the latter may be chosen from chlorine,bromine, fluorine or iodine.

When R₁ represents a saturated or unsaturated, mono- or polycyclicheterocyclic radical, it may for example be chosen from thienyl, furyl,pyridyl, dithiinyl, indolyl, isoindolyl, thiazolyl, isothiazolyl,oxazolyl, imidazolyl, pyrrolyl, triazolyl, thiadiazolyl, quinolyl,isoquinolyl or naphthyridinyl.

When R₁ represents a phenyl which is substituted by a chain carrying aheterocycle, the latter may be chosen from pyrrolidinyl, morpholino,piperidinyl, tetrahydropyridinyl, piperazinyl or thiomorpholino.

When R₃ is a halogen atom, it may be advantageously chosen from fluorineor chlorine.

Moreover, the products of general formula (I) have variousstereoisomeric forms, it is understood that the isoindole derivatives ofthe (3aR,7aR) form, in the pure state, or in the form of a mixture ofthe cis-(3aRS,7aRS) forms, are included within the scope of the presentinvention. When the radicals R₃ and R₄ are different, it is alsounderstood that the substituent R3 may be in the axial or equatorialposition and, therefore, that the R and S derivatives and mixturesthereof are also included within the scope of the present invention.Furthermore, when the symbol R₂ is other than the hydrogen atom, thesubstituted chain on the isoindole has a chiral centre, it is understoodthat the stereoisomeric forms and mixtures thereof are also includedwithin the scope of the present invention.

According to the invention, the perhydroisoindole derivatives of generalformula (I) may be obtained by reaction of the acid of general formula:##STR4## or of a reactive derivative of this acid, in which R₁ and R₂are defined as above, with an isoindole derivative of general formula:##STR5## in which the symbols R, R', R₃ and R₄ are defined as above,followed, where appropriate, by conversion of the amide obtained to anamidine.

It is understood that the amino, alkylamino or carboxyl radicalscontained in R₁ and/or R₂ are preferably protected beforehand. Theprotection is carried out using any compatible group whose introductionand removal does not affect the rest of the molecule. In particular theprocedure is carried out according to the methods described by T. W.Greene, Protective Groups in Organic Synthesis, A. Wiley--IntersciencePublication (1981), or by Mc Omie, Protective Groups in OrganicChemistry, Plenum Press (1973).

By way of example,

the amino or alkylamino groups may be protected with the followingradicals: methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl,allyloxycarbonyl, vinyloxycarbonyl, trichloroethoxycarbonyl,trichloroacetyl, trifluoroacetyl, chloroacetyl, trityl, benzhydryl,benzyl, allyl, formyl, acetyl, benzyloxycarbonyl or its substitutedderivatives;

the acidic groups may be protected with the following radicals: methyl,ethyl, t-butyl, benzyl, substituted benzyl or benzhydryl.

Furthermore, when R₂ represents a hydroxyl radical, it is preferable toprotect this radical beforehand. The protection is carried out forexample using an acetyl, trialkylsilyl or benzyl radical or in the formof a carbonate using a -COORa radical in which Ra is an alkyl or benzylradical.

When the condensation of a reactive derivative of the acid of generalformula (II) is carried out, the procedure is advantageously carried outusing the acid chloride, the anhydride, a mixed anhydride or a reactiveester in which the ester residue is a succinimido, an optionallysubstituted 1-benzotriazolyl, a 4-nitrophenyl, a 2,4-dinitrophenyl, apentachlorophenyl or a phthalimido radical.

The reaction is generally carried out at a temperature of between -40°and +40° C. in an organic solvent such as a chlorine-containing solvent(for example dichloromethane, dichloroethane, chloroform), a hydrocarbon(for example toluene), an ether (for example tetrahydrofuran, dioxane),an ester (for example ethyl acetate), an amide (for exampledimethylacetamide, dimethylformamide), or a ketone (for example acetone)or in a mixture of these solvents, in the presence of an acid acceptorsuch as a nitrogen-containing organic base such as for example pyridine,dimethylaminopyridine, N-methylmorpholine or a trialkylamine (inparticular triethylamine) or such as an epoxide (for example propyleneoxide). It is also possible to carry out the procedure in the presenceof a condensation agent such as a carbodiimide, [for exampledicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide], N,N'-carbonyldiimidazoleor 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline or alternatively in adilute organic medium in the presence of an alkaline condensation agentsuch as sodium bicarbonate, and where appropriate the amide obtained isthen converted to an amidine as defined above.

The conversion of the amide of general formula (I) to an amidine forwhich X is an NH radical is carried out by preparing the isoindoliumderivative of general formula: ##STR6## in which R, R', R₁, R₂, R₃ andR₄ are defined as above, Y represents a chlorine atom, a methoxy orethoxy radical and Z⁻ represents a chloride, tetrafluoroborate,fluorosulphonate, trifluoromethylsulphonate, methyl sulphate or ethylsulphate ion, and subsequently by reacting ammonia with the isoindoliumderivative.

It is understood that when R₃ is a hydroxyl, Y is other than a chlorineatom.

The preparation of the isoindolium derivative of general formula (IV) inwhich Y is a chlorine atom or a methoxy or ethoxy radical, is carriedout by reaction of a reagent such as phosgene, phosphorus oxychloride,phosphorus pentachloride, thionyl chloride, oxalyl chloride,trichloromethyl chloroformate, triethyl- or trimethyloxoniumtetrafluoroborate, methyl or ethyl triflate, methyl or ethylfluorosulphonate or methyl or ethyl sulphate. The reaction is carriedout in a chlorine-containing solvent (for example dichloromethane,dichloroethane) or in an aromatic hydrocarbon (for example toluene) at atemperature between 0° C. and the reflux temperature of the reactionmixture. The reaction of ammonia with the derivative of general formula(IV) is carried out in an anhydrous organic solvent such as achlorine-containing solvent (for example dichloromethane,dichloroethane) in an alcohol-chlorine-containing solvent mixture, in anether (for example tetrahydrofuran), in an ester (for example ethylacetate), in an aromatic solvent (for example toluene) or in a mixtureof these solvents, at a temperature between -20° C. and the refluxtemperature of the reaction mixture.

It is not essential to have isolated the isoindolium derivative ofgeneral formula (IV) in order to use it in this reaction.

According to the invention, the isoindole derivative of general formula(I), for which R₃ represents a halogen atom and R₄ represents a hydrogenatom, may also be obtained by halogenation of the correspondingderivative of the isoindole of general formula (I) for which R₃ is ahydroxyl radical, R4 is a hydrogen atom and X is an oxygen atom, andwhere appropriate, then converting the amide obtained to an amidine.

When it is desired to obtain a product for which R₃ represents afluorine atom, the reaction is advantageously carried out using afluorinating agent such as a sulphur fluoride [morpholinosulphurtrifluoride, sulphur tetrafluoride (J. Org. Chem., 40, 3808 (1975)),diethylaminosulphur trifluoride (Tetrahedron, 44, 2875 (1988)),phenylsulphur trifluoride (J. Am. Chem. Soc., 84, 3058 (1962)), such ashexafluoropropyldiethylamine (Japanese Patent 2,039,546) orN-(2-chloro1,1,2-trifluoroethyl)diethylamine, such as seleniumtetrafluoride (J. Am. Chem. Soc., 96,925 (1974) or such astetrafluorophenylphosphorane (Tet. Let., 907 (1973), by carrying out theprocedure in an organic solvent such as a chlorine-containing solvent(for example dichloromethane, dichloroethane), at a temperature between-30° and 30° C. It is understood that the use of an alcohol of the (S)configuration leads to the fluorine-containing derivative of the (R)configuration and that the use of an alcohol of the (R) configurationleads to the fluorine-containing derivative of the (S) configuration.

When it is desired to obtain a product for which R₃ represents achlorine atom, the chlorine-containing derivative of the (R)configuration may be obtained by treating the (S) alcohol withphosphorus pentachloride under the conditions defined by R. J. Cremlynet al., J. Chem. Soc., 3794 (1954); the chlorine-containing derivativeof the (S) configuration may be obtained by treating the (S) alcoholwith thionyl chloride under the conditions stated by R. J. Cremlyn inthe abovementioned reference.

According to the invention, the isoindole derivatives of general formula(I) for which R₃ is a hydroxyl radical and R₄ is a hydrogen atom, mayalso be obtained by reducing the isoindolone derivative of generalformula: ##STR7## in which R, R', R₁ and R₂ are defined as above,followed by the separation of the axial and equatorial isomers and bythe conversion of the amide obtained to an amidine.

The reduction is advantageously carried out using an alkali metalborohydride (sodium borohydride, lithium tri-s-butylborohydride) in asolvent such as an alcohol (for example methanol, ethanol) or an ether(tetrahydrofuran) in a basic medium, at a temperature between -20° and50° C.

According to the invention, the isoindole derivatives of general formula(I) for which X is an imino radical, may also be obtained from theisoindole derivative of general formula (III), by reaction of a productof general formula: ##STR8## optionally in the form of a salt, in whichR₁ and R₂ are defined as above and R'₅ represents an alkoxy radicalcontaining 1 to 4 carbon atoms in a linear or branched chain, or amethylthio, ethylthio, benzylthio or alkoxycarbonylmethylthio radical.

The reaction is carried out using the derivative of general formula(VI), which is optionally prepared in situ, in an organic solvent suchas a chlorine-containing solvent (for example dichloromethane,dichloroethane), an ether (for example tetrahydrofuran), an aromatichydrocarbon (for example toluene) or a nitrile, for exampleacetonitrile, at a temperature between 0° C. and the reflux temperatureof the reaction fixture.

It is understood that should the radicals R₁ and/or R₂ of the product ofgeneral formula (VI) carry substituents which may interfere with thereaction, these substituents should be protected beforehand.

The acids of general formula (II) may be prepared according to themethods described below, in the examples, or by analogy with thesemethods.

The isoindole derivative of general formula (III) for which R₃ is ahalogen atom and R₄ is a hydrogen or halogen atom, may be prepared byhalogenation of an isoindole of the general formula: ##STR9## in which Rand R' are defined as above, R₅ is a protective radical, R'₃ is ahydroxyl radical and R'₄ a hydrogen atom if it is desired to obtain amonohalogenated isoindole derivative, or alterntively R'₃ and R'₄,together form an oxo radical if it is desired to obtain a dihalogenatedisoindole derivative, followed by removal of the protective radical R₅.

The protective radical R₅ may be any amino-protecting group which iscompatible with the reaction and whose introduction and removal does notaffect the rest of the molecule. Alkoxycarbonyl groups,benzyloxycarbonyl groups, optionally substituted benzyl groups, formyl,chloroacetyl, trichloroacetyl, trifluoroacetyl, vinyloxycarbonyl,phenoxycarbonyl, 1-chloroethoxycarbonyl or chlorocarbonyl groups may bementioned by way of example.

When it is desired to obtain a fluorine-containing perhydroisoindolederivative of general formula (III), the fluorination is carried outunder the conditions described above for the fluorination of aderivative of general formula (I) in which R₃ is hydroxyl, at atemperature between -30° and +30° C. It is understood that thefluorine-containing derivative of the (R) configuration is obtained froman alcohol of the (S) configuration and that the fluorine-containingderivative of the (S) configuration is obtained from the hydroxylatedderivative of the (R) configuration. It is also possible to carry outthe procedure using a mixture of alcohols of the (R) and (S)configurations and to carry out the separation with respect to thederivative of general formula (III).

When it is desired to obtain the difluorine-containing derivative ofgeneral formula (III), the reaction is carried out using the isoindoloneof general formula (VII) (R'₃ and R'₄, together, form an oxo radical),by carrying out the procedure under the conditions defined above, at atemperature between 30° C. and the reflux temperature of the reactionmixture.

When it is desired to obtain a chlorine-containing perhydroisoindolederivative of general formula (III), the chlorination is carried outaccording to the conditions described by R. J. Cremlyn et al., J. Chem.Soc., 3794 (1954), either by means of phosphorus pentachloride using thehydroxylated derivative of the (S) configuration when it is desired toobtain the chlorine-containing derivative of the (R) configuration, orby means of thionyl chloride using the hydroxylated derivative of the(S) configuration when it is desired to obtain a chlorine-containingderivative of the (S) configuration. It is understood that theseparation may also be carried out with respect to the product ofgeneral formula (III).

When it is desired to obtain the dichlorine-containing derivative, theprocedure is carried out using perhydroisoindole of general formula(VII), by treatment with phosphorus pentachloride under the conditionsmentioned above.

Subsequent removal of the protective radical R₅ is carried out accordingto the usual methods, in particular according to the methods describedby T. W. Greene, by A. Wiley or by Mc Omie in the abovementionedreferences.

The isoindole derivative of general formula (III) for which R₃ is ahalogen atom and R₄ is a hydrogen atom, may also be obtained byhalogenation of a perhydroisoindole derivative of general formula:##STR10## in which R and R' are defined as above, followed by removal ofthe protective radical R₅.

The halogenation is carried out using a quaternary ammonium halide suchas for example tetrabutylammonium fluoride or using an alkali metalhalide such as for example potassium fluoride or caesium fluoride, inanhydrous medium, in an organic solvent such as an ether (for exampletetrahydrofuran, dioxane), a chlorine-containing solvent (for exampledichloromethane) or in a mixture of solvents, at a temperature between-30° and 50° C.

It is understood that the sulphonylated derivative of general formula(VIIa) of the (S) configuration leads to a halogenated derivative of the(R) configuration and that the sulphonylated derivative of the (R)configuration leads to a halogenated derivative of the (S)configuration.

The removal of the radical R₅ is carried out as described above.

The sulphonylated derivative of general formula (VIIa) may be obtainedby treating the perhydroisoindole derivative of general formula (VII),for which R'₃ is a hydroxyl radical and R'₄ is a hydrogen atom, with areactive trifluoromethanesulphonic acid derivative.

The reaction is generally carried out by reaction oftrifluoromethanesulphonic anhydride in the presence of pyridine, in achlorine-containing solvent (for example dichloromethane), at atemperature of about 30° C.

The perhydroisoindole derivative of general formula (VII) may beprepared by protecting the amino of the corresponding derivative ofgeneral formula: ##STR11## in which R, R', R'₃ and R'₄ are defined asfor the general formula (VII).

The protection is carried out according to the usual methods, inparticular according to the references mentioned above.

The perhydroisoindole derivative of general formula (VII) or (VIII), forwhich R'₃ is a hydroxyl radical and R'₄ is a hydrogen atom, may beobtained by reduction of the corresponding perhydroisoindole derivativeof general formula (VII) or (VIII) for which R'₃ and R'₄, together, forman oxo radical

The reduction is carried out under conditions similar to those describedfor the production of the perhydroisoindoles of general formula (I), forwhich R₃ is hydroxyl, from the corresponding perhydroisoindolone.

The hydroxylated perhydroisoindole derivative of general formula (III)or (VIII), for which R'₃ is a hydroxyl radical and R'₄ is a hydrogenatom, may be obtained by releasing the protective radical R₅ from thecorresponding perhydroisoindole derivative of general formula (VII) inwhich R'₃ and R'₄ are defined as above.

The removal is carried out using known methods which do not affect therest of the molecule.

The isoindole derivative of general formula (VIII), for which R'₃ andR'₄ together form an oxo radical, may be obtained from the correspondingderivative of general formula: ##STR12## in which R and R' are definedas above and R₆ represents an allyl radical or a radical of thestructure --CR_(a) R_(b) R_(c) in which R_(a) and R_(b) are hydrogenatoms or phenyl radicals which are optionally substituted (by a halogenatom, an alkyl, alkoxy or nitro radical), and R_(c) is defined as R_(a)and R_(b) or represents an alkyl or alkoxyalkyl radical, at least one ofR_(a), R_(b) and R_(c) being a substituted or unsubstituted phenylradical and the alkyl radicals containing 1 to 4 carbon atoms in alinear or branched chain, by removing the radical R₆ by any known methodwhich does not affect the rest of the molecule.

In particular, when R is a hydrogen atom, and when R₆ is other than anallyl radical, the group R₆ may be removed by catalytic hydrogenation inthe presence of palladium. Generally, the reaction is carried out in anacidic medium, in a solvent such as an alcohol (methanol, ethanol), inwater or directly in acetic acid or formic acid, at a temperaturebetween 20° and 60° C.

When R₆ is a benzhydryl or trityl radical, the removal may be carriedout by treatment in an acidic medium, by carrying out the procedure at atemperature of between 0° C. and the reflux temperature of the reactionmixture, in an alcohol, in an ether, in water or directly in aceticacid, formic acid or trifluoroacetic acid. The group R₆ may also beremoved by reaction of vinyl chloroformate, 1-chloroethyl chloroformateor phenyl chloroformate, a product of general formula: ##STR13## inwhich R and R' are defined as above, and R₇ is a vinyl, 1-chloroethyl orphenyl radical, being obtained as an intermediate, and then by removingthe radical --COOR₇ by acid treatment. The reaction of the chloroformateis generally carried out in an organic solvent such as achlorine-containing solvent (for example dichloromethane,dichloroethane, chloroform), an ether (for example tetrahydrofuran,dioxane) or a ketone (for example acetone) or in a mixture of thesesolvents, by carrying out the procedure at a temperature of between 20°C. and the reflux temperature of the reaction mixture.

The removal of the radical --COOR₇ is carried out by treatment in anacidic medium for example with trifluoroacetic, formic,methanesulphonic, p-toluene-sulphonic, hydrochloric or hydrobromic acidin a solvent such as an alcohol, an ether, an ester, a nitrile, amixture of these solvents or in water, at a temperature between 0° C.and the reflux temperature of the reaction mixture.

Under the conditions for removing the --COOR₇ radicals mentioned above,the isoindolone derivative of general formula (VIII) is obtained in theform of a salt of the acid used, which may be used directly in thesubsequent stage.

The isoindolone derivative of general formula (IX) (or (VII) when R'₃and R'₄ together form an oxo radical and R₅ is an optionally substitutedbenzyl radical), may be obtained by cycloaddition reaction, by reactionof a silylated derivative of general formula: ##STR14## in which R₆ isdefined as above, (R°)₃ represents alkyl radicals or alkyl and phenylradicals and R°° represents an alkoxy, cyano or phenylthio radical, withthe cyclohexenone derivative of general formula: ##STR15## in which Rand R' are defined as above.

The procedure is carried out in the presence of a catalytic amount of anacid chosen from trifluoroacetic acid, acetic acid, methanesulphonicacid or the acids given in the references mentioned below, in an organicsolvent such as a chlorine-containing solvent (for exampledichloromethane, dichloroethane), in an aromatic hydrocarbon, in anitrile (acetonitrile) or in an ether, at a temperature between 0° C.and the reflux temperature of the reaction mixture.

The silylated derivative of general formula (XI) may be obtainedaccording to the methods described by:

Y. Terao et al., Chem. Pharm. Bull., 33, 2762 (1985);

A. Hosomi et al., Chem. Lett., 1117 (1984)

A. Padwa et al., Chem. Ber., 119, 813 (1986) or

Tetrahedron, 41, 3529 (1985).

It is understood that the perhydroisoindole derivatives of generalformula (I), (III), (V), (VII), (VIIa), (VIII), (IX) and (X) haveseveral stereoisomeric forms. When it is desired to obtain a product ofgeneral formula (I) of the (3aR,7aR) form, the separation of theisomeric forms is preferably carried out with respect to the derivativeof general formula (VIII) for which R'₃ and R'₄ together form an oxoradical. It may also be carried out with respect to the derivative ofgeneral formula (III). The separation is carried out according to anyknown method which is compatible with the molecule.

By way of example, the separation may be carried out by the preparationof an optically active salt, by reaction of L(+) or D(-)-mandelic acid,or of dibenzoyltartaric acid, followed by separation of the isomers bycrystallization. The desired isomer is released from its salt in a basicmedium.

The separation of the axial and equatorial isomers of the hydroxylatedderivatives or of the halogenated derivatives is advantageously carriedout with respect to the products of general formula (VII) or (VIII), theprocedure being carried out by crystallization and chromatography. It isalso possible to carry out the procedure with respect to the products ofgeneral formula (III) or (I).

The new isoindole derivatives of general formula (I) may be purified,where appropriate, by physical methods such as crystallization orchromatography.

Where appropriate, the new derivatives of general formula (I), for whichthe symbols R₁ and/or R₂ contain amino or alkylamino substituents and/orX represents an NH radical, may be converted to the addition salts withacids. As examples of addition salts with pharmaceutically acceptableacids, there may be mentioned the salts formed with inorganic acids(hydrochlorides, hydrobromides, sulphates, nitrates, phosphates) or withorganic acids (succinates, fumarates, tartrates, acetates, propionates,maleates, citrates, methanesulphonates, p-toluenesulphonates,isethionates, or with substituted derivatives of these compounds).

The new isoindole derivatives of general formula (I) may also, whereappropriate, when R₂ represents a carboxyl radical, be converted to themetal salts or to the addition salts with a nitrogen-containing base,according to methods which are known per se. These salts may be obtainedby reaction of a metal base (for example alkali metal or alkaline earthmetal), of ammonia or an amine, with a product according to theinvention, in an appropriate solvent such as an alcohol, an ether orwater, or by exchange reaction with an organic acid salt. The saltformed precipitates after optional concentration of the solution, it isseparated by filtration, decantation or freeze-drying. As examples ofpharmaceutically acceptable salts, there may be mentioned salts withalkali metals (sodium, potassium, lithium) or with alkaline earth metals(magnesium, calcium), ammonium salt, salts of nitrogen-containing bases(ethanolamine, diethanolamine, trimethylamine, triethylamine,methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine,benzylamine, dicyclohexylamine, N-benzyl-β-phenethylamine,N,N'-dibenzylethylenediamine, diphenylenediamine, benzhyldrylamine,quinine, choline, arginine, lysine, leucine, dibenzylamine).

The new isoindole derivatives according to the present invention whichantagonise the effects of substance P may find an application in thefields of analgesia, inflammation, asthma, allergies, on the centralnervous system, on the cardiovascular system, as antispasmodic, or onthe immune system, as well as in the domain of the stimulation oflachrymal secretions.

Indeed, the products according to the invention exhibit an affinity forsubstance P receptors at doses of between 5 and 2000 nM according to thetechnique described by C. M. Lee et al., Mol. Pharmacol., 23, 563-69(1983).

Furthermore, it has been demonstrated, using various products, that itis a substance P-antagonizing effect. In the technique described by S.Rosell et al., Substance P, Ed. by US Von Euler and B. Pernow, RavenPress, New York (1977), pages 83 to 88, the products studied proved tobe active at doses of between 20 and 1000 nM.

Substance P is known to be involved in a certain number of pathologicaldomains:

Agonists and antagonists of substance P, A. S. Dutta Drugs of thefuture, 12 (8), 782 (1987);

Substance P and pain: an updating, J. L. Henry, TINS, 3(4), 97 (1980);

Substance P in inflammatory reactions and pain, S. Rosell, Actual. Chim.Ther., 12th series, 249 (1985);

Effects of Neuropeptides on Production of Inflammatory Cytokines byHuman Monocytes, M. Lotz et al., Science, 241, 1218 (1988);

Neuropeptides and the pathogenesis of allergy, Allergy, 42, 1 to 11(1987);

Substance P in Human Essential Hypertension, J. CardiovascularPharmacology, 10 (suppl. 12), 5172 (1987).

The study of a number of products has demonstrated in particular thatthe new isoindole derivatives exhibit an analgesic activity according tothe technique of Siegmund E. et al., Proc. Soc. Exp. Biol. Med., 95, 729(1957).

    ______________________________________                                        Product of                                                                    general formula (I)                                                                           ED.sub.50 mg/kg p.o.                                          ______________________________________                                        Example 1       3                                                             Example 2       2                                                             Example 7       1.5                                                           ______________________________________                                    

The study of a number of isoindole derivatives of general formula (I)according to the technique of A. Saria et al., Arch. Pharmacol., 324,212-218 (1983) adapted to mice, has made it possible to demonstrate aninhibitory effect of the increase in capillary permeability broughtabout by septide (agonist of substance P), which is evidence of ananti-inflammatory activity:

    ______________________________________                                        Product of                                                                    general formula (I)                                                                           ED.sub.50 mg/kg s.c.                                          ______________________________________                                        Example 1       0.70                                                          Example 2       0.30                                                          Example 7       0.32                                                          ______________________________________                                    

Injection of substance P into animals produces hypotension. The productsstudied in the technique of C. A. Maggi et al., J. Auton. Pharmac., 7,11-32 (1987) exhibit an antagonistic effect in rats towards thishypotension. In particular, the products administered at a dose of 1mg/kg i.v./min, for 5 min, produce antagonism of the hypotension inducedby an i.v. injection of 250 mg/kg of substance P.

    ______________________________________                                        Product of      % inhibition                                                  general formula (I)                                                                           of hypotension                                                ______________________________________                                        Example 1       73                                                            Example 2       68                                                            ______________________________________                                    

Moreover, the isoindole derivatives according to the present inventionare not toxic, they proved to be nontoxic in mice by the subcutaneousroute at a dose of 40 mg/kg or by the oral route at a dose of 100 mg/kg.

The products of general formula (I) in which:

the radicals R are hydrogen atoms,

the symbols R' are phenyl radicals,

the symbol X represents an oxygen atom or an NH radical,

the symbol R₁ represents a phenyl radical which is optionallysubstituted by an alkoxy radical which may be optionally substituted [bya dialkylamino radical or a dialkylamino radical whose alkyl parts formwith the nitrogen atom to which they are attached, a heterocycle with 5to 6 members], or substituted by a dialkylamino radical whose alkylparts may form with the nitrogen atom to which they are attached, aheterocycle as defined above,

the symbol R₂ represents a hydrogen atom or an alkyl radical,

the symbol R₃ represents a fluorine or chlorine atom or a hydroxylradical, and

the symbol R₄ represents a hydrogen atom or, together with R₃,represents a fluorine atom, are of particular interest.

And among these products, the following products are more particularlyadvantageous:

2-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenyl-7-fluoroperhydroisoindole,

4,4-diphenyl-7-fluoro-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindole

2-{[2-(3-dimethylaminopropoxy)phenyl]acetyl}-4,4-diphenyl-7-fluoroperhydroisoindole,

7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolol,

2-[(2-methoxyphenyl)acetyl]-4,4-diphenyl-7-fluoroperhydroisoindole,

in their stereoisomeric forms as well as mixtures thereof and, whereappropriate, their salts.

EXAMPLES

The following examples, which are given with no limitation beingimplied, illustrate the present invention.

In the examples below, it is understood, unless specifically stated,that the proton NMR spectra were established at 250 MHz in dimethylsulphoxide; the chemical shifts are expressed in ppm.

EXAMPLE 1

A solution of 0.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in50 cm³ of dry dichloromethane is added over 10 minutes to a solution,cooled to +4° C., of 0.72 g of(3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole, 0.5 g of2-(3-dimethylaminopropoxy)phenylacetic acid, 0.03 g of1-hydroxybenzotriazole in 75 cm³ of dichloromethane, followed by 0.37cm³ of diisopropylethylamine. The reaction mixture is stirred for 3hours at 0° C. and then washed twice with 50 cm³ of water and twice with50 cm³ of a saturated solution of sodium chloride. The organic phase isdried over magnesium sulphate and concentrated to dryness under reducedpressure (2.7 kPa). The residue is taken up in 21 cm³ of 0.1Nhydrochloric acid, 50 cm³ of diethyl ether and 30 cm³ of water. Theaqueous phase is separated and freeze-dried to give 0.85 g of(3aR,7R,7aR)-2-{[2-(3-dimethylaminopropoxy)phenyl]acetyl}-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride, in the form of a white freeze-dried product.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3060, 3030, 2960,2890, 2800, 2200, 1635, 1605, 1495, 1460, 1445, 1250, 755, 705.

Proton NMR spectrum (DMSO-d₆) (at room temperature, a mixture of the tworotamers is observed): 0.95-1.35 and 1.8-2.1 (2mt, 2×1H, CH₂ in 6);2.6-2.8 (mt, 6H, N(CH₃)₂); 3.9 and 4.05 (2mt, 2×1H, OCH₂); 4.8 and 4.85(broad 2d, J=50, 1H, CHF); 6.8 to 7.5 (mt, 14H, aromatics).

(3aR,7R,7aR)-4,4-Diphenyl-7-fluoroperhydroisoindole hydrochloride may beobtained in the following manner:

A solution of 2.25 g of(3aR,7R,7aR)-2-t-butoxycarbonyl-4,4-diphenyl-7-fluoroperhydroisoindolein 25 cm³ of dioxane is treated with a 5.8N solution of hydrochloricacid in dioxane and stirred for 2 hours at 20° C. and then concentratedto dryness under reduced pressure (2.7 kPa). The residue is concentratedby adding 100 cm³ of isopropyl oxide, the solid is filtered and dried togive 1.8 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride, in the form of a cream-colored powder. Proton NMRspectrum (DMSO-d₆): 1.0-1.35 (mt, 1H of CH₂ in 6); 4.9 (broad d, J=50,1H, CHF); 7.1 to 7.5 (mt, 14H, aromatics); 9.05 and 9.9 (2 mf, 2×1H, NH₂⁺).

(3aR,7R,7aR)-2-t-Butoxycarbonyl-4,4-diphenyl-7-fluoroperhydroisoindolemay be obtained in the following manner:

A solution of 4.87 g of(3aR,7S,7aR)-2-t-butoxy-carbonyl-4,4-diphenyl-7-trifluoromethylsulphonyloxy-perhydroisoindolein 150 cm³ of dry dichloromethane is treated with 22.6 cm³ of a 1Msolution of tetrabutylammonium fluoride in tetrahydrofuran and thenstirred for 17 hours at 20° C. and concentrated to dryness under reducedpressure (2.7 kPa). The residue is chromatographed on a silica gelcolumn (particle size 0.2-0.063 mm, diameter 4.5 cm, height 35 cm),eluting under a nitrogen pressure of 0.4 bar with a cyclohexane andethyl acetate mixture (75/25) and collecting fractions of 20 cm³.Fractions 28 to 38 are pooled and concentrated to dryness under reducedpressure (2.7 kPa) to give 1.44 g of(3aR,7R,7aR)-2-t-butoxycarbonyl-4,4-diphenyl-7-fluoro-perhydroisoindole,in the form of white crystals; melting point 200° C., [α]_(D) ²⁰ =-225°(c= 1, CHCl₃).

(3aR,7S,7aR)-2-t-Butoxycarbonyl-4,4-diphenyl-7-trifluoromethylsulphonyloxyperhydroisoindolemay be obtained in the following manner:

1.5 cm³ of pyridine are added to a solution, cooled to -30° C., of 6.7 gof (3aR,4S,7aR)-2-t-butoxycarbonyl-7,7-diphenyl-4-perhydroisoindolol in100 cm³ of dry dichloromethane, followed, over 10 minutes, with asolution of 3.2 g of trifluoromethanesulphonic anhydride in 25 cm³ ofdry dichloromethane. The reaction mixture is stirred for 2 hours at -30°C. and then diluted with 250 cm³ of water and 100 cm³ ofdichloromethane. The organic phase is washed with 200 cm³ of a saturatedsolution of sodium bicarbonate and with 200 cm³ of a saturated solutionof sodium chloride and then dried and concentrated to dryness underreduced pressure (2.7 kPa) to give 8.6 g of(3aR,7S,7aR)-2-t-butoxycarbonyl-4,4-diphenyl-7-trifluoromethylsulphonyl-oxyperhydroisoindole,in the form of a yellow meringue which is used as it is in subsequentstages of the synthesis.

(3aR,4S,7aR)-2-t-Butoxycarbonyl-7,7-diphenyl-4-perhydroisoindolol may beobtained in the following manner:

10.55 g of di-tert-butyl dicarbonate are added to a solution of 13 g of(3aR,4S,7aR)-7,7-diphenyl-4-perhydroiso-indolol and 0.5 g of4-dimethylaminopyridine in 450 cm³ of dichloromethane. After stirringfor 2 hours at 25° C., the reaction mixture is concentrated to drynessunder reduced pressure (2.7 kPa) and the residue is crystallized from 50cm³ of ethyl ether. 9 g of(3aR,4S,7aR)-2-t-butoxycarbonyl-7,7-diphenyl-4-perhydroisoindolol areobtained in the form of white crystals; melting point 190° C.

(3aR,4S,7aR)-7,7-Diphenyl-4-perhydroisoindolol may be obtained in thefollowing manner:

7.18 g of a solution of sodium borohydride in 500 cm³ of methanolsupplemented with 20 drops of a concentrated solution of sodiumhydroxide (20 drops) is added over 90 minutes to a solution, cooled to5° C., of 100 g of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolonehydrochloride in 1000 cm³ of absolute methanol. After stirring for 2.5hours between 5 and 10° C., the crystals formed are drained and taken upin 900 cm³ of water and 1000 cm³ of ethyl ether. The solution isfiltered and alkalised with 15 cm³ of a 4N solution of sodium hydroxideand then stirred for 2 h at 5° C. The crystals formed are drained,washed with ethyl ether and dried to give 28.8 g of(3aR,7S,7aR)-7,7-diphenyl-4-perhydroisoindolol in the form of whitecrystals; melting point 205° C., [α]_(D) ²⁰ =-230° (c=1, CHCl₃).

(3aR,7aR)-7,7-Diphenyl-4-perhydroisoindolone hydrochloride may beprepared in the following manner:

500 cm³ of a 4N aqueous sodium hydroxide are slowly added, withstirring, to a suspension of 200 g of(3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride in 2000 cm³of ethyl acetate; the stirring is continued until dissolution of thestarting product. The organic solution is washed with 250 cm³ ofdistilled water, with 250 cm^(a) of a saturated aqueous solution ofsodium chloride, dried over magnesium sulphate and filtered. A solutionof 92.8 g of L(+)-mandelic acid in 1000 cm³ of ethyl acetate is added,with stirring, to the solution thus obtained; after stirring for 4hours, the crystals obtained are drained, washed with 250 cm³ of ethylacetate (twice) and dried. The crystals are taken up in 2000 cm³ ofdistilled water; the mixture is refluxed, with stirring, for 15 minutes;the insoluble crystals are drained, washed with 100 cm³ of distilledwater (twice) and dried. They are recrystallized from a mixture of 1100cm³ of acetonitrile and 500 cm³ of distilled water; the crystalsobtained are drained, washed with 40 cm³ of acetonitrile (3 times) anddried. 80 g of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone(L)-mandelate are obtained; [α]_(D) ²⁰ =-164° (c= 1, methanol).

400 cm³ of 1N aqueous sodium hydroxide and 600 cm³ of ethyl acetate areadded to 80 g of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone(L)-mandelate; the mixture is stirred at room temperature untildissolution of the starting product; the organic solution is washed with250 cm³ of distilled water, with 250 cm³ of a saturated aqueous solutionof sodium chloride, dried over magnesium sulphate and filtered; it isacidified, with stirring, by adding 30 cm ³ of 9N hydrochloric acid; thecrystals obtained are drained, washed with 50 cm³ of ethyl acetate(twice), with 50 cm³ of isopropyl oxide and dried. 52.3 g of(3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride are obtained;melting point 270° C., with decomposition; [α]_(D) ²⁰ =-282° (c=0.5,methanol).

(3aRS,7aRS)-7,7-Diphenyl-4-perhydroisoindolone hydrochloride may beprepared according to the following method:

150 g of (3aRS,7aRS)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone, 1500cm³ of methanol and 450 cm³ of 1N hydrochloric acid are added to 15 g of10% palladium on charcoal; the reaction mixture is hydrogenated, withstirring, at room temperature and at atmospheric pressure. Thetheoretical volume of hydrogen was absorbed after 5 hours of reaction;the reaction mixture is filtered and then concentrated to dryness underreduced pressure (2.7 kPa); the residue is crystallized from 200 cm³ ofethanol; the crystals obtained are drained, washed with 50 cm³ ofethanol and dried. 110 g of(3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride areobtained; melting point 270° C., with decomposition.

Proton NMR spectrum: 2.03 (Mt, 1H, 1H of H in 5 or 6); 2.3 (Mt, 1H, 1Hof --H in 5 or 6); 2.48 (DD, partially masked, 1H of --CH₂ -- in 1);2.69 (DD, 1H, 1H of --CH₂ -- in 1); 2.8 (Mt, 2H, --CH₂ -- in 6 or 5);3.34 (DD, partially masked, 1H of --CH₂ -- in 3); 3.5 (Mt, 1H, --CH-- in3a); 3.82 (DD, 1H, 1H of --CH₂ -- in 3); 3.95 (Mt, 1H, --CH-- in 7a);7.15 to 7.65 (Mt, 10H, aromatics); 9.43 (Mf, 2H, --NH₂ --Cl). Infraredspectrum (KBr) characteristic bands in cm⁻¹ : 3600-3300, 3100-3000,3000-2850, 3100-2400, 1715, 1595, 1580, 1495, 1470, 1445, 775, 750, 705.

(3aRS,7aRS)-2-Benzyl-7,7-diphenyl-4-perhydroisoindolone may be preparedin the following manner:

5 drops of trifluoroacetic acid are added to a solution of 155 g of4,4-diphenyl-2-cyclohexen-1-one and 202 cm³ ofN-butoxymethyl-N-trimethylsilylmethylbenzylamine in 1000 cm³ of drydichloromethane and the reaction mixture is refluxed for 45 minutes. 50cm³ of N-butoxy-methyl-N-trimethylsilylmethylbenzylamine and 3 drops oftrifluoroacetic acid are added and the mixture is further stirred for 45minutes under reflux before again adding 25 cm³ ofN-butoxymethyl-N-trimethylsilyl-methylbenzylamine and 3 drops oftrifluoroacetic acid. The reaction mixture is stirred under reflux for45 minutes and then treated with 50 g of potassium carbonate, filteredand concentrated to dryness under reduced pressure (2.7 kPa). Theresidue is dissolved in 200 cm³ of isopropyl oxide and the solution iscooled at 0° C. for 1 hour. The crystals are drained, washed twice with15 cm³ of isopropyl oxide and dried to give 193 g of (3aRS,7aRS)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone in the form of whitecrystals; melting point 132° C.

N-Butoxymethyl-N-trimethylsilylmethylbenzylamine may be preparedaccording to the method of Y. Terao et al., Chem. Pharm. Bull., 33, 2762(1985).

EXAMPLE 2

0.04 g of hydroxybenzotriazole hydrate is added to a solution, cooled to+5° C., of 1 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride and 0,924 g of2-{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetic acid in 40 cm³ of drydichloromethane followed by 0.79 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.51 cm³of diisopropylethylamine. After stirring for 2.5 hours at +5° C. and 20hours at 20° C., the reaction mixture is washed twice with 50 cm³ ofwater, dried over magnesium sulphate and then concentrated to dryness at40° C. under reduced pressure (2.7 kPa). The residue is chromatographedon a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm,height 31 cm), eluting under a nitrogen pressure of 0.5 bar with anethyl acetate, acetic acid and water mixture (60/10/10 by volume) andcollecting fractions of 25 cm³. Fractions 11 to 31 are pooled andconcentrated to dryness under reduced pressure (2.7 kPa). The residue istaken up in 20 cm³ of dichloromethane, the solution is washed with 20cm³ of a 1N aqueous solution of sodium hydroxide and then dried overmagnesium sulphate and concentrated to dryness. This wash with a basicsolution is repeated again. 0.68 g of(3aR,7R,7aR)-2-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenyl-7-fluoroperhydro-isoindoleis obtained in the form of a white solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3085, 3055, 3035,2950, 2875, 2785, 1640, 1600, 1495, 1455, 1440, 1245, 750, 700. ProtonNMR spectrum (DMSO-d₆ +CF₃ COOD): 1.1-1.45 (mt, 1H, 1H in 6); 1.9 (mt,4H, 2CH₂ in 3 and 4 of pyrrolidino); 2.27 (mt, 1H, 1H in 5); 3.77 (d,J=10, 1H, H in 1); 4.03 (mt, 2H, OCH₂); 4.78 (broad d, J=50, 1H, CHF);7.1 to 7.5 (mt, 14H, aromatics).

The hydrochloride salt of {[3-(1-pyrrolidinyl)-2-propoxy]phenyl}aceticacid may be prepared in the following manner:

700 cm³ of a 6N solution of hydrochloric acid are added to 24.9 g ofmethyl {[3-(1-pyrrolidinyl)-2-propoxy]-phenyl}acetate. After refluxingfor 2 hours, the solution is concentrated to dryness at 50° C. underreduced pressure. The residue is then taken up in 100 cm³ of toluene andthe solution is then concentrated to dryness under reduced pressure.After an identical treatment with toluene, 21.9 g of the hydrochloridesalt of {[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetic acid are obtainedin the form of a beige solid; melting point 173° C.

Proton NMR spectrum (250 MHz, DMSO-d₆): 1.8 to 2.1 (mt, 4H, --N(CH₂CH₂)₂); 2.15 (mt, 2H, CH₂ --CH₂ --CH₂); 2.98 and 3.52 (2mt, 2×2H,--N(CH₂ CH₂)₂); 3.26 (mt, 2H, CH₂ --N<); 3.5 (2s, 2H, CH₂ COO); 4.06 (t,J=6, 2H, OCH₂); 6.32 (mt, 2H, aromatics in 3 and 5); 7.23 (mt, 2H,aromatics in 4 and 6); 11.2 (mf, 1H, --NH^(+<)).

Methyl {[3-(1-pyrrolidinyl)-2-propoxy]-phenyl}acetate may be prepared inthe following manner:

18.4 g of potassium carbonate, 4.5 g of sodium iodide and then 9.54 g ofpyrrolidine are successively added to a solution of 36 g of methyl2-(3-bromopropoxy)phenyl-acetate in 400 cm³ of acetonitrile. Thereaction mixture is refluxed for 5 hours and then stirred at 20° C. for20 hours and diluted with 800 cm³ of dichloromethane. The solution iswashed with 80 cm³ of water and then twice with 80 cm³ of brine. Thechloromethylenic phase is dried over sodium sulphate and concentrated todryness under reduced pressure. The residue is chromatographed on asilica gel column (particle size 0.04-0.06 mm, diameter 4.5 cm, height48 cm), eluting under a nitrogen pressure of 0.4 bar with an ethylacetate and methanol mixture (90/10 by volume) and collecting fractionsof 500 cm³. Fractions 3 to 8 are pooled and concentrated to dryness at50° C. under reduced pressure (2.7 kPa). 24.9 g of methyl{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetate are obtained in the formof an orange-colored oil.

Infrared spectrum (CCl₄, characteristic bands, cm⁻¹): 3065, 3030, 2950,2930, 2880, 2790, 1740, 1600, 1585, 1490, 1770, 1455, 1430, 1250.

Methyl 2-(3-bromopropoxy)phenylacetate may be prepared in the followingmanner:

254.5 g of potassium carbonate and 654 cm³ of 1,3-dibromopropane areadded to a solution of 153 g of methyl (2-hydroxyphenyl)acetate in 1400cm³ of acetonitrile. The suspension obtained is refluxed for 20 hours,cooled to 20° C. and then filtered The filtrate is concentrated todryness at 50° C. under reduced pressure. The residue is chromatographedon a silica gel column (particle size 0.04-0.06 mm, diameter 8.8 cm,height 43 cm), eluting under a nitrogen pressure of 0.5 bar with acyclohexane and ethyl acetate mixture (95/5 by volume) and collectingfractions of 300 cm³. Fractions 18 to 53 are pooled and concentrated todryness under reduced pressure (2.7 kPa). 130.6 g of methyl2-(3-bromopropoxy)phenylacetate are obtained in the form of anorange-coloured oil.

Proton NMR spectrum (250 MHz, CDCl₃): 2.32 (qt, J=6.5, 2H, CH₂ --CH₂--CH₂); 3.26 (t, J=6.5, 2H, CH₂ Br); 3.65 (s, 2H, COOCH₃); 3.7 (s, 2H,CH₂ COO); 4.13 (t, J=6.5, 2H, OCH₂); 6.94 (mt, 2H, aromatics in 3 and5); 7.25 (mt, 2H, aromatics in 4 and 6).

EXAMPLE 3

By carrying out the procedure as in Example 9 below, using 0.16 g of2-dimethylaminophenylacetic acid and 0.30 g of(3aR,7S,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, 0.11g of(3aR,7S,7aR)-2-[(2-dimethyl-aminophenyl)acetyl]-4,4-diphenyl-7-fluoroperhydroiso-indoleis obtained in the form of a white meringue.

Infrared spectrum (KBr, characteristic bands, cm⁻¹) 3090, 3060, 3030,2940, 2875, 2825, 2770, 1645, 1595, 1580, 1495, 1450, 1420, 755, 730,700. Proton NMR spectrum (at room temperature, a mixture of the tworotamers is observed): 2.35 and 2.58 (2s, 6H, N(CH₃)2), 4.2-4.6 (mt, 1H,CHF), 6.9-7.5 (mt, 14H, aromatics).

(3aR,7S,7aR)-4,4-Diphenyl-7-fluoroperhydroisoindole hydrochloride may beprepared in the following manner:

By carrying out the procedure as in Example 8 below, using 0.5 g of(3aR,7S,7aR)-2-tert-butyloxy-carbonyl-4,4-diphenyl-7-fluoroperhydroisoindole,0.35 g of (3aR,7S,7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride is obtained in the form of a grey solid. Infrared spectrum(KBr, characteristic bands, cm⁻¹): 3420, 3090, 3050, 3025, 2970, 2920,2800-2250, 1590, 1580, 1495, 1460, 1445, 1060, 750, 730, 700.

(3aR,7S,7aR)-2-tert-Butyloxycarbonyl-4,4-diphenyl-7-fluoroperhydroisoindolemay be prepared in the following manner:

A solution of 0.37 cm³ of 4-trifluorothiomorpholine in 10 cm³ of drydichloromethane is added to a solution, cooled to +5° C., of 1.0 g of(3aR,4R,7aR)-2-tert-butyloxycarbonyl-7,7-diphenyl-4-perhydroisoindololin 20 cm³ of dry dichloromethane. After stirring for 2 hours at +5° C.,the reaction mixture is washed with 20 cm³ of a 5% aqueous solution ofsodium bicarbonate and then dried over magnesium sulphate andconcentrated to dryness under reduced pressure (2.7 kPa). The residue ischromatographed on a silica gel column (particle size 0.04 mm-0.06 mm,diameter 2.4 cm, height 35 cm), eluting under a nitrogen pressure of 0.8bar with a cyclohexane and ethyl acetate mixture (90/10 by volume) andcollecting fractions of 25 cm³. Fractions 25 to 34 are pooled andconcentrated to dryness. 0.27 g of(3aR,7S,7aR)-2-tert-butyloxycarbonyl-4,4-diphenyl-7-fluoroperhydroiso-indoleis obtained in the form of a white meringue.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3090, 3060, 3030,2975, 2930, 2875, 1695, 1595, 1580, 1495, 1450, 1405, 1365, 1175, 755,730, 700.

EXAMPLE 4

0.28 cm³ of triethylamine and 0.32 g of carbonyldiimidazole are added toa solution, cooled to 4° C., of 0.57 g of the hydrobromide salt of(2-pyrrolidinophenyl)acetic acid in 20 cm³ of dry dichloromethane. Themixture is stirred for one hour at +4° C. and then a solution of 0.67 gof (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in20 cm³ of dry dichloromethane and 0.28 cm³ of triethylamine, is added.The reaction mixture is stirred at room temperature for 24 hours andthen diluted with 100 cm³ of dichloromethane, washed twice with 50 cm³of water, dried over magnesium sulphate, filtered and concentrated todryness under reduced pressure (2.7 kPa). The residue is chromatographedon a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm,height 38 cm), eluting under a nitrogen pressure of 0.5 bar with acyclohexane and ethyl acetate mixture (70/30 by volume) and collectingfractions of 20 cm³. Fractions 26 to 54 are pooled and concentrated todryness under reduced pressure (2.7 kPa). The residue is crystallizedfrom an acetonitrile and diisopropyl oxide mixture (25/75 by volume).0.16 g of(3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[(2-pyrrolidinophenyl)acetyl]perhydroisoindoleis obtained in the form of white crystals; melting point 170° C.

EXAMPLE 5

0.17 g of carbonyldiimidazole is added to a solution, cooled to +4° C.,of 0.19 g of (2-dimethylaminophenyl)-acetic acid in 15 cm³ of drydichloromethane. The mixture is stirred for one hour at +4° C. and thena solution of 0.35 g(3aR,7R,7aR)-7-chloro-4,4-diphenylperhydro-isoindole hydrochloride in 10cm³ of dry dichloromethane is then added followed by a solution of 0.15cm³ of triethylamine in 10 cm³ of dry dichloromethane. The reactionmixture is stirred at room temperature for 20 hours and then dilutedwith 120 cm³ of dichloromethane, washed with 80 cm³ of water and thenwith a saturated aqueous solution of sodium chloride, dried overmagnesium sulphate, filtered and concentrated to dryness under reducedpressure (2.7 kPa). The residue is chromatographed on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm),eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate andcyclohexane mixture (75/25 by volume) and collecting fractions of 20cm³. Fractions 6 to 9 are pooled and concentrated to dryness underreduced pressure (2.7 kPa). The product, which is obtained in the formof a base, is converted to the hydrochloride by dissolving in 25 cm³ ofethyl ether, followed by the addition of 5 cm³ of a 3.2N solution ofhydrochloric acid to the ethyl ether, washing with ethyl ether anddrying. 0.14 g of(3aR,7R,7aR)-7-chloro-2-[(2-dimethylamino-phenyl)acetyl]-4,4-diphenylperhydroisoindolehydrochloride is obtained in the form of white crystals; melting point190° C.

(3aR,7R,7aR)-7-Chloro-4,4-diphenylperhydroisoindole hydrochloride may beobtained in the following manner:

A solution of 0.4 g of(3aR,7R,7aR)-7-chloro-2-chlorocarbonyl-4,4-diphenylperhydroisoindole in6 cm³ of a 1N aqueous solution of hydrochloric acid and 14 cm³ oftetrahydrofuran is heated at 80° C. for 9 hours, with stirring. Thereaction mixture is concentrated to dryness under reduced pressure (2.7kPa). 0.35 g of (3aR,7R,7aR)-7-chloro-4,4-diphenylperhydroisoindolehydrochloride is obtained in the form of a white solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3055, 3025, 3000,2250, 1600, 1495, 1580, 1460, 1445, 1435, 760, 750, 735, 700.

(3aR,7R,7aR)-7-Chloro-2-chlorocarbonyl-4,4-diphenylperhydroisoindole maybe obtained in the following manner:

1.3 g of calcium carbonate and then 2 g of phosphorus pentachloride aresuccessively added to a solution, cooled to +4° C., of 1 g of(3aR,4S,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindololin 60 cm³ of chloroform, and the mixture is stirred at room temperaturefor 20 hours. The reaction mixture is then filtered, diluted with 80 cm³of chloroform, washed twice with 80 cm³ of water, dried over magnesiumsulphate and concentrated to dryness under reduced pressure (2.7 kPa).The residue is chromatographed on a silica gel column (particle size0.04-0.06 mm, diameter 2.5 cm, height 34 cm), eluting under a nitrogenpressure of 0.4 bar with a cyclohexane and ethyl acetate mixture (30/70by volume) and collecting fractions of 20 cm³. Fractions 7 to 10 arepooled and concentrated to dryness under reduced pressure (2.7 kPa).0.44 g of (3aR,7R,7aR)-7-chloro-2-chlorocarbonyl-4,4-diphenylperhydroisoindole isobtained in the form of a white solid.

Infrared spectrum (CCl₄ solution, characteristic bands, cm⁻¹): 3090,3065, 3035, 2930, 2855, 1745, 1600, 1585, 1495, 1450, 700.

EXAMPLE 6

0.39 g of carbonyldiimidazole is added to a solution, cooled to +4° C.,of 0.43 g of (2-dimethylaminophenyl)-acetic acid in 15 cm³ of drydichloromethane. The mixture is stirred for one hour at +4° C. and thena solution of 0.84 g of(3aR,7S,7aR)-7-chloro-4,4-diphenylperhydro-isoindole hydrochloride in 10cm³ of dry dichloromethane is then added followed by a solution of 0.34cm³ of triethylamine in 10 cm³ of dry dichloromethane. The reactionmixture is stirred at room temperature for 20 hours and then dilutedwith 100 cm³ of dichloromethane, washed with 50 cm³ of water and thenwith a saturated aqueous solution of sodium chloride, dried overmagnesium sulphate, filtered and concentrated to dryness under reducedpressure (2.7 kPa). The residue is chromatographed on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 23 cm),eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate andcyclohexane mixture (25/75 by volume) and collecting fractions of 80cm³. Fraction 2 is concentrated to dryness under reduced pressure (2.7kPa). The product, which is obtained in the form of a base, is convertedto the hydrochloride by dissolving in 4 cm³ of acetonitrile followed bythe addition of 6 cm³ of a 3.2N solution of hydrochloric acid in ethylether, washing with isopropyl ether and drying. 0.08 g of(3aR,7S,7aR)-7-chloro-2-[(2-dimethylamino-phenyl)acetyl]-4,4-diphenylperhydroisoindolehydrochloride is obtained in the form of a beige solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3055, 3025, 2950,1635, 1490, 1460, 1440, 760, 750, 700. Proton NMR spectrum (DMSO-d₆) (at403° K., a mixture of the two rotamers is observed, DMSO-d₆ +CF₃ COOD,main signals): 3 and 3.13 (2s, 6H, N(CH₃)2); 4.54 and 4.63 (2mt, 1H,CHCl); 7 to 7.8 (mt, 14H, aromatics).

(3aR,7S,7aR)-7-Chloro-4,4-diphenylperhydroisoindole hydrochloride may beobtained in the following manner:

10 cm³ of a 6.3N solution of hydrochloric acid in dioxane are added to asolution of 1.03 g of(3aR,7S,7aR)-2-tert-butyloxycarbonyl-7-chloro-4,4-diphenylperhydroisoindolein 5 cm³ of dioxane. The reaction mixture is stirred at room temperaturefor 2 hours and then concentrated to dryness under reduced pressure (2.7kPa). 0.84 g of (3aR,7S,7aR)-7-chloro-4,4-diphenyl-perhydroisoindolehydrochloride is obtained in the form of a solid which is used in thecrude state in the next test.

(3aR,7S,7aR)-2-tert-Butyloxycarbonyl-7-chloro-4,4-diphenylperhydroisoindolemay be obtained in the following manner:

A solution of 1 g of(3aR,4S,7aR)-2-tert-butyloxycarbonyl-7,7-diphenyl-4-perhydroisoindololin 10 cm³ of thionyl chloride is stirred for 3 hours at 80° C. Thereaction mixture is then concentrated to dryness under reduced pressure(2.7 kPa). 1.03 g of(3aR,7S,7aR)-2-tert-butyloxycarbonyl-7-chloro-4,4-diphenylperhydroisoindoleare obtained in the form of a solid which is used in the crude state inthe next test.

EXAMPLE 7

0.32 g of carbonyldiimidazole is added to a solution, cooled to +4° C.,of 0.36 g of (S)-2-(2-methoxyphenyl)-propionic acid in 20 cm³ of drydichloromethane. The mixture is stirred for one hour at +4° C. and thena solution of 0.67 g of(3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydro-isoindole hydrochloride in 20cm³ of dry dichloromethane and 0.28 cm³ of triethylamine, is added. Thereaction mixture is stirred at room temperature for 20 hours, dilutedwith 200 cm³ of dichloromethane and then washed with 50 cm³ of water,dried over magnesium sulphate, filtered and concentrated to drynessunder reduced pressure (2.7 kPa). The residue is chromatographed on asilica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 20cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetateand cyclohexane mixture (60/40 by volume) and collecting fractions of 20cm³. Fractions 10 to 15 are pooled and concentrated to dryness underreduced pressure (2.7 kPa). The residue is crystallized from 0.6 cm³ ofisopropyl oxide. The crystals obtained are drained, washed withisopropyl oxide and then dried. 0.19 g of(3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindoleis obtained in the form of white crystals; melting point 195° C.

(3aR,7R,7aR)-4,4-Diphenyl-7-fluoroperhydroisoindole hydrochloride may beobtained in the following manner:

40 cm³ of a 6.3N solution of hydrochloric dioxane are added to asolution of 3.7 g of(3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-tert-butyloxycarbonylperhydro-isoindolein 40 cm³ of dioxane, and the mixture is stirred at room temperature for2 hours. The reaction mixture is concentrated to dryness under reducedpressure (2.7 kPa), triturated in diisopropyl oxide, filtered and dried.3.1 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride are obtained in the form of white crystals; melting point200° C., with decomposition.

(3aR,7R,7aR)-4,4-Diphenyl-7-fluoro-2-tert-butyloxycarbonylperhydroisoindolemay be obtained in the following manner:

A solution of 3.5 cm³ of morpholinosulphur trifluoride in 50 cm³ ofdichloromethane is added to a solution, cooled to +5° C., of 9.4 g of(3aR,4S,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindololin 250 cm³ of dry dichloromethane. The reaction mixture is stirred for 4hours at +5° C. and then diluted with 300 cm³ of dichloromethane, washedwith 250 cm³ of an aqueous solution of sodium hydrogen carbonate, driedover magnesium sulphate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). The residue is chromatographed on a silicagel column (particle size 0.04-0.06 mm, diameter 3.5 cm, height 42 cm),eluting under a nitrogen pressure of 0.5 bar with a cyclohexane andethyl acetate mixture (90/10 by volume) and collecting fractions of 120cm³. Fractions 13 to 17 are pooled and concentrated to dryness underreduced pressure (2.7 kPa). The residue is crystallized fromcyclohexane. 2.55 g of(3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-tert-butyloxycarbonylperhydroisoindoleare obtained in the form of white crystals; melting point 202° C.

(S)-2-(2-Methoxyphenyl)propionic acid may be obtained in the followingmanner:

(S)-2-(2-Methoxyphenyl)propionic acid may be prepared by analogy withthe methods described by D. A. Evans et al., Tetrahedron, 44, 5525,(1988), according to the following procedure:

1.52 g of lithium hydroxide are added to a solution, cooled to +5° C.,of 4.1 g of(4S,5S)-4-methyl-5-phenyl-3-[(S)-2-(2-methoxyphenyl)-propionyl]-2-oxazolidinonein 60 cm³ of tetrahydrofuran and 30 cm³ of water. The reaction mixtureis stirred for 3 hours at this temperature and then, afterre-equilibrating to room temperature, ethyl acetate is added, themixture is decanted and the aqueous phase is acidified with a 1N aqueoussolution of hydrochloric acid, extracted with ethyl acetate and theorganic phase is dried over magnesium sulphate and concentrated todryness under reduced pressure (2.7 kPa). The solid obtained isrecrystallized from hexane, drained and dried. 0.4 g of(S)-2-(2-methoxyphenyl)-propionic acid is obtained in the form of whitecrystals; melting point 102° C. [α]_(D) ²⁰ =+84.6° (c=1; CHCl₃).

(4S,5S)-4-Methyl-5-phenyl-3-[(S)-2-(2-methoxphenyl)propionyl]-oxazolidinonemay be obtained in the following manner:

19.1 g of sodium 1,1,1,3,3,3-hexamethyldisilazanate are added to asolution, cooled to -50° C., of 10 g of(4S,5S)-4-methyl-5-phenyl-3-[(2-methoxyphenyl)acetyl]-2-oxazolidinone in150 cm³ of tetrahydrofuran and the mixture is stirred for 45 minutes atthis temperature and then 7.72 cm³ of methyl iodide are added. Thereaction mixture is then stirred for 15 hours at room temperature andthen diluted with ethyl acetate, washed with 50 cm³ of water and thenwith 50 cm³ of a saturated aqueous solution of sodium chloride, driedover magnesium sulphate and concentrated to dryness under reducedpressure (2.7 kPa). The residue obtained is crystallized from isopropyloxide, drained and dried. 4.2 g of(4S,5S)-4-methyl-5-phenyl-3-[(S)-2-(2-methoxyphenyl)-propionyl]-2-oxazolidinoneare obtained in the form of a white solid.

(4S,5S)-4-Methyl-5-phenyl-3-(2-methoxyphenylacetyl)-2-oxazolidinone maybe obtained in the following manner:

9.38 g of 2-methoxyphenylacetic acid are added to a suspension of 1.89 gof sodium hydride (80% 25 dispersion in vaseline) in 200 cm³ of drytetrahydrofuran, at room temperature. This suspension is cooled to -30°C., 7.77 cm³ of pivaloyl chloride are added and then a solution, cooledto -78° C., which is obtained by adding 35.27 cm³ of a 1.6M solution ofbutyllithium in hexane to a solution, cooled to -78° C., of 10 g of(4S,5S)-4-methyl-5-phenyl-2-oxazolidinone in 200 cm³ of drytetrahydrofuran is finally added. The reaction mixture is stirred for 45minutes at -30° C. and then after re-equilibrating to room temperature,200 cm³ of a saturated aqueous solution of ammonium chloride are addedfollowed by 500 cm³ of ethyl acetate; after decantation, the organicphase is washed twice with 100 cm³ of water and then twice with 100 cm³of a saturated aqueous solution of sodium chloride; dried over magnesiumsulphate and concentrated to dryness under reduced pressure (2.7 kPa).The residue is chromatographed on a silica gel column (particle size0.04-0.06 mm, diameter 4.8 cm, height 36 cm), eluting under a nitrogenpressure of 0.6 bar with a cyclohexane and ethyl acetate mixture (85/15followed by 80/20 by volume) and collecting fractions of 50 cm³.Fractions 14 to 31 are pooled and concentrated to dryness under reducedpressure (2.7 kPa). 13.6 g of(4S,5S)-4-methyl-5-phenyl-3-(2-methoxyphenylacetyl)-2-oxazolidinone areobtained in the form of a yellow oil.

EXAMPLE 8

By carrying out the procedure as in Example 9 below, using 0.77 g of2-dimethylaminophenylacetic acid and 1.50 g of(3aRS,7aRS)-4,4-diphenyl-7,7-difluoroperhydroiso-indole hydrochloride,1.29 g of(3aRS,7aRS)-2-[(2-dimethylaminophenyl)acetyl]-4,4-diphenyl-7,7-difluoro-perhydroisoindoleare obtained in the form of a white solid; melting point 189° C.

(3aRS,7aRS)-4,4-Diphenyl-7,7-difluoroperhydroisoindole hydrochloride maybe prepared in the following manner:

20 cm³ of dioxane and 20 cm³ of 6.3N hydrochloric acid are added to 1.8g of(3aRS,7aRS)-2-tert-butyloxy-carbonyl-4,4-diphenyl-7,7-difluoroperhydroisoindole.After stirring for 20 hours at room temperature, the white suspensionobtained is concentrated to dryness at 40° C. under reduced pressure(2.7 kPa). The residue is washed with diisopropyl oxide, the solidobtained is drained and then dried. 1.51 g of(3aRS,7aRS)-4,4-diphenyl-7,7-difluoroperhydroisoindole hydrochloride areobtained in the form of a white solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3090, 3050, 3025,2965, 2935, 2900, 2800-2250, 1595, 1580, 1495, 1465, 1445, 760, 730,700. Proton NMR spectrum (DMSO-d₆ +CF₃ COOD): 1.2-1.55 and 2.12 (2mt,2×lH, C₂ in 6); 3-3.3 (mt, 1H, H in 7a); 3.58 (mt, 2H, CH₂ in 1); 3.76(mt, 1H, H in 3a); 7.1 to 7.5 (mt, 10H, aromatics).

(3aRS,7aRS)-2-tert-Butyloxycarbonyl-4,4-diphenyl-7,7-difluoroperhydroisoindolemay be prepared in the following manner:

A solution of 5.0 g of(3aRS,7aRS)-2-tert-butyloxycarbonyl-7,7-diphenyl-4-perhydroisoindolonein 30 cm³ of dry dichloromethane is added to a solution of 3.4 cm³ ofdiethylaminosulphur trifluoride in 20 cm³ of dry dichloromethane. Afterstirring for 5 hours under reflux, and 20 hours at 20° C., the reactionmixture is washed with 50 cm³ of a saturated aqueous solution of sodiumbicarbonate and with 50 cm³ of water and then dried over magnesiumsulphate and concentrated to dryness. The residue is chromatographed ona silica gel column (particle size 0.04-0.06 mm, diameter 2.8 cm, height35 cm), eluting under a nitrogen pressure of 0.8 bar with a cyclohexaneand ethyl acetate mixture (95/5 followed by 90/10 by volume) andcollecting fractions of 25 cm³. Fractions 24 to 52 are pooled andconcentrated to dryness under reduced pressure (2.7 kPa). The residue iscrystallized from ethyl acetate and diisopropyl oxide, the crystals aredrained and then dried. 1.80 g of(3aRS,7aRS)-2-tert-butyloxycarbonyl-4,4-diphenyl-7,7-difluoroperhydroisoindoleare obtained in the form of white crystals; melting point 162° C.

EXAMPLE 9

0.49 g of N,N'-carbonyldiimidazole is added to a solution of 0.52 g of2-dimethylaminophenylacetic acid in 20 cm³ of dry dichloromethane. Themixture is stirred for 30 minutes at +5° C. and then a solution of 0.93g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride and0.84 cm³ of triethylamine in 10 cm³ of dichloromethane, is added. Thereaction mixture is stirred for 2 hours at +5° C. and then washed with10 cm³ of water, dried over magnesium sulphate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is chromatographed on a silica gel column (0.04 mm-0.06 mm,diameter 2 cm, height 35 cm), eluting with ethyl acetate and collectingfractions of 30 cm³. Fractions 8 to 27 are pooled, concentrated todryness under reduced pressure (2.7 kPa). The residue iscrystallised-from a mixture of 4 cm³ of acetonitrile and 20 cm³ of ethylether. The crystals are drained and dried under reduced pressure (2.7kPa). 0.70 g of(3aR,4S,7aR)-2-[(2-dimethylaminophenyl)-acetyl]-7,7-diphenyl-4-perhydroisoindololis obtained in the form of a white solid; melting point 160° C., [α]_(D)²⁰ =-162° (c=0.5, methanol).

EXAMPLE 10

By carrying out the procedure as in Example 9, using 0.26 g of2-dimethylaminophenylacetic acid and 0.50 g of(3aR,4R,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride, 0.21 g of(3aR,4R,7aR)-2-[(2-dimethylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindololis obtained in the form of a white solid; melting point 204° C., [α]_(D)²⁰ =-212° (c=0.5, methanol).

(3aR,4R,7aR)-7,7-Diphenyl-4-perhydroisoindolol hydrochloride may beprepared by hydrogenation of a suspension of 0.70 g of(3aR,4R,7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolol in 30 cm³ ofmethanol and 2.0 cm³ of 1N hydrochloric acid, at atmospheric pressurefor 20 hours at 20° C. in the presence of 0.12 g of 20% palladiumhydroxide on carbon black. The reaction mixture is filtered andconcentrated to dryness under reduced pressure (2.7 kPa), the oilobtained is concreted with ethyl ether. The suspension is filtered, andthe solid drained and dried under reduced pressure (2.7 kPa). 0.52 g of(3aR,4R,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride is obtainedin the form of a white solid; melting point 220° C. (withdecomposition).

Infrared spectrum (characteristic bands, c⁻¹): 3400, 3090, 3050, 3025,3000-2800, 1600, 1580, 1495, 1465, 985, 750, 700. Proton NMR spectrum(DMSO-d₆, main signals): 1.06 (broad t, J=14, 1H, H in 5); 1.66 (broadd, J=14, 1H, H in 5); 2.17 (broad d, J=14, 1H, CH₂ in 6); 3.8 (broad s,1H, H in 4); 5.3 (mf, 1H, OH); 7.05 to 7.45 (mt, 10H, aromatics); 8.4and 9.43 (mf, 2H, NH₂ ⁺).

(3aR,4R,7aR)-2-Benzyl-7,7-diphenyl-4-perhydroisoindolol may be preparedin the following manner:

4.0 cm³ of a 1M solution of lithium tri-sec-butylboro-hyride intetrahydrofuran is added over 5 minutes to a solution, cooled to 0° C.,of 1.3 g of (3aR,7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone in 6.0cm³ of tetrahydrofuran. After stirring for 3 hours at 0° C., 0.5 cm³ ofthe 1M solution of borohydride is again added to the reaction mixture.After 1 hour at 0° C., followed by the addition of 50 cm³ of water and50 cm³ of ethyl acetate, the organic phase is decanted, washed with 20cm³ of water, dried over magnesium sulphate and concentrated to drynessunder reduced pressure (2.7 kPa). The oil obtained is crystallized from30 cm³ of diisopropyl oxide, the crystals are drained and dried underreduced pressure (2.7 kPa). 0.70 g of(3aR,4R,7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolol is obtained inthe form of white crystals; melting point 154° C.

(3aR,7aR)-2-Benzyl-7,7-diphenyl-4-perhydroisoindolone may be prepared inthe following manner:

7.9 cm³ of benzyl bromide are added to a solution, cooled to 0° C., of21.7 g of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride in300 cm³ of dichloromethane, and 18.5 cm³ triethylamine. After stirringfor 1 hour at 0° C. and 2 hours at 20° C., the reaction mixture iswashed with 50 cm³ of water, dried 15 over magnesium sulphate andconcentrated to dryness under reduced pressure (2.7 kPa). The residue ischromatographed on a silica gel column (0.04-0.06 mm, diameter 5 cm,height 40 cm), eluting of 250 cm³ under a nitrogen pressure of 0.6 barwith an ethyl acetate and cyclohexane mixture (75/25 by volume) andcollecting fractions of 250 cm³. Fractions 3 to 6 are pooled andconcentrated to dryness under reduced pressure (2.7 kPa). 22.1 g(3aR,7aR)-7,7-benzyl-4-perhydroisoindolone are obtained in the form of awhite solid; melting point 124° C. [α]_(D) ²⁰ =-279°.

EXAMPLE 11

0.42 cm³ of triethylamine and 0.49 g of carbonyl-diimidazole are addedto a solution, cooled to +4° C., of 0.86 g of the hydrobromide salt of(2-pyrrolidinophenyl)acetic acid in 20 cm³ of dry dichloromethane. Themixture is stirred for one hour at 4° C. and then a solution of 1 g of(3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride and 0.42cm³ of triethylamine in 10 cm³ of dry dichloromethane, is added. Thereaction mixture is stirred at room temperature for 24 hours, and thenwashed twice with 10 cm³ of water and then with an aqueous solution ofsodium hydrogen carbonate, dried over magnesium sulphate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). The product,which is obtained in the form of a base, is converted to thehydrochloride by dissolving in the minimum amount of acetone, bytreating with a solution of hydrochloric acid in ethyl ether, and byadding ethyl ether. The solid obtained is triturated in ethyl ether andthen dried. 0.2 g of(3aR,4S,7aR)-7,7-diphenyl-2-[(2-pyrrolidinophenyl)acetyl]-4-perhydroisoindololhydrochloride is obtained in the form of a beige solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3085, 3050, 3025,2945, 2880, 2750, 2250, 1640, 1600, 1495, 1445, 1060, 755, 730, 700.Proton NMR spectrum (DMSO-d₆): 0.92 and 1.72 (2 mt, 2×1H, CH₂ -- in 5);2.17 (mt, 4H, 2 CH₂ in 3 and 4 of pyrrolidino); 7 to 7.8 (mt, 14H,aromatics).

EXAMPLE 12

By carrying out the procedure as described above in Example 9, using1.82 g of (2-methoxyphenyl)acetic acid and 3.29 g of(3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride, 3.9 g of(3aR,4S,7aR)-2-[(2-methoxyphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindololare obtained in the form of a white solid; melting point 246° C. [α]_(D)²⁰ =-174° (c=0.37; methanol)

EXAMPLE 13

0.37 g of carbonyldiimidazole is added to a solution, cooled to +4° C.,of 0.41 g of (S)-2-(2-methoxyphenyl)-propionic acid in 15 cm³ of drydichloromethane. The mixture is stirred for one hour at 4° C. and then asolution of 0.75 g (3aR,4S,7aR)-7,7-diphenyl-4-perhydroiso-indololhydrochloride is added. The reaction mixture is stirred at roomtemperature for 20 hours and then then washed twice with 10 cm³ ofwater, dried over magnesium sulphate, filtered and concentrated todryness under reduced pressure (2.7 kPa). The residue is chromatographedon a silica gel column (particle size 0.04-0.06 mm, diameter 3.6 cm,height 37 cm), eluting under a nitrogen pressure of 0.5 bar with anethyl acetate and cyclohexane mixture (50/50 by volume) and collectingfractions of 50 cm³. Fractions 21 to 41 are pooled and concentrated todryness under reduced pressure (2.7 kPa). The residue is triturated inisopropyl oxide and then dried. 0.3 g of(3aR,4S,7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindololis obtained in the form of a white meringue.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3090, 3060, 3030,2940, 2875, 2840, 1630, 1600, 1495, 1445, 1245, 1060, 755, 730, 700.Proton NMR spectrum (DMSO-d₆) (at room temperature, a mixture of the tworotamers is observed): 0.9-1.8 (mt, 2H, CH₂ in 5); 1.14 and 1.23 (2d,J=7, 3H, CH₃); 3.55 mixture of the two rotamers is observed): 0.09-1.8(mt, 2H, CH₂ in 5); 1.14 and 1.23 (2d, J=7, 3H, CH₃ ; 3.55 and 3.65 (2s,3H, OCH₃); 3.85 and 4.23 (2mt, 1H, --COCHCH₃ --); 6.8 to 7.5 (mt, 14H,aromatics).

(3aR,4S,7aR)-7,7-Diphenyl-4-perhydroisoindolol hydrochloride may beobtained in the following manner:

40 cm³ of a 6.3N solution of hydrochloric dioxane are added to asolution of 2 g of(3aR,4S,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindololin 20 cm³ of dioxane, and the mixture is stirred at room temperature for5 hours. The reaction mixture is concentrated to dryness under reducedpressure (2.7 kPa), triturated in acetonitrile, filtered and dried. 1.57g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride areobtained in the form of white crystals; melting point 266° C.

(3aR,4S,7aR)-7,7-Diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindololand(3aR,4R,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindololmay be obtained in the following manner:

A solution of 1 g of sodium borohydride in 200 cm³ of methanol is addeddropwise over 40 minutes to a solution, cooled to +4° C. of 17.8 g of(3aR,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolone inone liter of methanol, followed by 10 drops of caustic soda. Thereaction mixture is stirred for 3 hours at +4° C. and then 2 cm³ of a0.1N aqueous solution of hydrochloric acid are added and the mixture isconcentrated to dryness under reduced pressure (2.7 kPa). The residue isdissolved in 350 cm³ of dichloromethane, washed with 100 cm³ of waterand then with 50 cm³ of a saturated solution of sodium chloride, driedover magnesium sulphate, and concentrated to dryness under reducedpressure (2.7 kPa). The residue is crystallized from 40 cm³ of ethylether. The crystals obtained are drained and dried. 8.4 g of(3aR,4S,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindololare obtained in the form of white crystals; melting point 190° C. Thecrystallization mother liquors are concentrated to dryness under reducedpressure (2.7 kPa). The residue is chromatographed on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 4 cm, height 33 cm),eluting under a nitrogen pressure of 0.4 bar with a dichloromethane andmethanol mixture (96/4 by volume) and collecting fractions of 20 cm³.Fractions 18 to 21 are pooled and concentrated to dryness under reducedpressure (2.7 kPa). 1.88 g of(3aR,4R,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindololare obtained in the form of a white meringue. Fractions 26 to 31 arepooled and concentrated to dryness under reduced pressure (2.7 kPa). Theresidue is crystallized from 5 cm³ of ethyl ether. 2.88 g of(3aR,4S,7aR)-7,7-diphenyl-tert-butyloxycarbonyl-4-perhydroisoindolol areadditionally obtained in the form of white crystals; melting point 190°C.

(3aR,7aR)-7,7-Diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolone maybe obtained in the following manner:

0.74 g of 4-dimethylaminopyridine and then 14.7 g of di-tert-butyldicarbonate are successively added to a solution of 20 g of(3aR,7aR)-7,7-diphenyl-4-perhydroiso-indolone hydrochloride in 100 cm³of dry dichloromethane and 6.17 cm^(a) of triethylamine. The reactionmixture is stirred for 24 hours at room temperature and then washed withan aqueous solution of citric acid and then with an aqueous solution ofsodium hydrogen carbonate, dried over magnesium sulphate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). The residue iscrystallized from 90 cm³ of ethyl ether. The crystals are drained,washed with 10 cm³ of ethyl ether and then dried. 14.1 g of(3aR,7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolone areobtained in the form of white crystals; melting point 119° C.

EXAMPLE 14

0,766 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is added to asolution, cooled to 10° C., of 1 g of(3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol, 0.97 g of2-(3-dimethylaminopropoxy)phenylacetic acid and 0.05 g of1-hydroxybenzotriazole in 50 cm³ of dichloromethane. The reactionmixture is stirred for 90 minutes 20° C. and then washed twice with 50cm³ of water and with 50 cm³ of a saturated solution of sodium chloride.The organic phase is dried over magnesium sulphate and concentrated todryness under reduced pressure (2.7 kPa). The residue is chromatographedon a silica gel column (particle size 0.2-0.063 mm, diameter 2.9 cm,height 23 cm), eluting under a nitrogen pressure of 0.7 bar with1,2-dichloroethane and methanol mixtures (1 liter at 90/10 by volume and1.5 liters at 70/30 by volume) and collecting fractions of 25 cm³.Fractions 10 to 84 are pooled and concentrated to dryness under reducedpressure (2.7 kPa) to give 1.1 g of(3aR,4S,7aR)-2-{[2-(3-dimethylaminopropoxy)phenyl]-acetyl}-7,7-diphenyl-4-perhydroisoindololin the form of a cream-colored meringue.

Infrared spectrum (KBr, characteristics bands, cm⁻¹): 3080, 3050, 3020,2940, 2870, 2815, 2765, 1635, 1600, 1490, 1455, 1445, 1245, 1065, 750,730, 700. Proton NMR spectrum (DMSO-d₆) at 433° K.: 1.06 and 1.76 (2mt,2×1H, CH₂ in 5); 2.27 (s, 6H, N(CH₃)₂); 3.9 (d, J=11, 1H, 1H of CH₂ in3); 6.8 to 7.5 (mt, 14H, aromatics).

A solution of 100 g of 2-hydroxyphenylacetic acid, 75 cm³ of benzylalcohol and 0.5 g of paratoluenesulphonic acid in 1400 cm³ of toluene isrefluxed for 2 hours while removing the water formed. After cooling,treating with 3 g of animal black and filtering, the reaction mixture isconcentrated to 150 cm³ and 300 cm³ of isopropyl oxide are added. Thecrystals obtained by cooling to 0° C. are drained, washed and dried togive 82.5 g of benzyl 2-hydroxyphenylacetate. 174 g of potassiumcarbonate are added to a solution of 153 g of this ester in a mixture of500 cm³ of 1,3-dibromopropane and 2500 cm³ of acetonitrile, and themixture is refluxed for 17 hours. The reaction mixture is cooled,filtered and concentrated to dryness under reduced pressure (2.7 kPa).The residue is taken up in 500 cm³ of ethyl acetate and the organicphase is washed with 400 cm³ of water twice and twice with 250 cm³ of asaturated solution of sodium chloride and then dried and concentrated todryness under reduced pressure (2.7 kPa). The residue is chromatographedon a silica gel column (particle size 0.2-0.063 mm, diameter 9 cm,height 55 cm), eluting with a cyclohexane and ethyl acetate mixture(95/5 by volume) and collecting fractions of 500 cm³. Fractions 12 to 18are pooled and concentrated to dryness under reduced pressure (2.7 kPa)to give 90 g of benzyl 2-(3-bromopropoxy)phenyl-acetate in the form of ayellow oil. A solution of 40 g of this product in 500 cm³ ofacetonitrile is heated in an autoclave with 27 g of sodium iodide and 90g of dimethylamine for 16 hours at 80° C. The reaction mixture iscooled, filtered and concentrated to dryness under reduced pressure (2.7kPa). The residue is purified by acid-base treatment to give 29.3 g ofbenzyl 2-(3-dimethylaminopropoxy)phenylacetate in the form of a yellowoil. Hydrogenation of this ester, at atmospheric pressure at 40° C. inethyl acetate in the presence of palladium hydroxide followed bycrystallization from ethyl acetate, yield 17.5 g of2-(3-dimethylaminopropoxy)phenylacetic acid in the form of whitecrystals; melting point 98° C.

EXAMPLE 15

By carrying out the procedure as in Example 2, but using thehydrochloride salt of [2-(3-isopropylaminopropoxy)phenyl]acetic acid and(3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, ayellow oil is obtained after purification by chromatography on a Mercksilica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 25cm), eluting under a nitrogen pressure of 0.5 bar with a dichlormethaneand methanol mixture (90/10 by volume) and collecting fractions of 20cm³. The hydrochloride salt of this oil yields(3aR,7R,7aR)-2-[[[3-(1-isopropylamino)-2-propoxy]phenyl]acetyl]-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride in the form of a chestnut-colored solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3090+3060+3030,2950+2885, 2860-2250, 1640, 1605+1495, 1455+1445, 1245, 750+700. ProtonNMR spectrum (250 MHz, DMSO, δ in ppm and J in Hz): (at roomtemperature, a mixture of the two rotamers is observed ); 1 to 1.35 (mt,1H, axial H of CH₂ in 6); 1.18 and 1.25 (2d, J=7, 6H, CH₃ isopropyl);1.8 to 2.1 (mt, H of CH₂ in 6 and CH₂ in a); 2.27 (broad d, J=13.5, 1H,equatorial H of CH₂ in 5); 2.4 to 4 (mt, H of CH₂ in 5, CH₂ in 3, CH₂ in1, CH in 3a, CH in 7a, NCH); 3.02 (mt, 2H, NCH₂ in b); 3.3 to 3.54 (2s,2H, NCOCH₂ Ar); 3,9 to 4.15 (mt, 2H, OCH₂); 4.76 and 4.8 (broad 2d,J=50, 1H, CHF); 6.7 to 7.5 (mt, 14H, H aromatics).

EXAMPLE 16

By carrying out the procedure as in Example 2, but using thehydrochloride salt of [2-(3-benzylaminopropoxy)phenyl]acetic acid and(3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, ayellow oil is obtained after purification by chromatography on a Mercksilica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 25cm), eluting under a nitrogen pressure of 0.5 bar with an ethyl acetateand methanol mixture (95/5 by volume) and collecting fractions of 20cm³. The acid oxalate of this oil yields(3aR,7R,7aR)-2-[[[3-(1-benzylamino)-2-propoxy]phenyl]acetyl]-4,4-diphenyl-7-fluoroperhydroisoindole,acid oxalate in the form of a chestnut-coloured solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3090+3060+3030,2955+2885, 3250-2250, 1780+1720, 1640, 1625, 1605+1498, 1455+1445, 1245,750+700. Proton NMR spectrum (250 MHz, DMSO, δ in ppm and J in Hz): (atroom temperature, a mixture of the two rotamers is observed); 1 to 1.4(mt, 1H, axial H of CH₂ in 6); 1.8 to 4.2 (mt, other H of CH₂ in 6, CH₂in 5, CH₂ in 3, CH₂ in 1, CH in 3a and CH in 7a, OCH₂ --CH₂ --CH₂ N);3.27 and 3.53 (2s, 2H, HCOCH₂ Ar); 4.1 and 4.18 (2s, 2H, NCH2Ar), 4.78and 4.81 (2dmt, J=50, 1H, CH--F); 6.7 to 7.6 (mt, 19H, aromatics).

EXAMPLE 17

By carrying out the procedure as in Example 2, but using 1.26 g of thehydrochloride salt of [2-(3-diethylaminopropoxy)phenyl]acetic acid and1.2 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride, 1.5 g of(3aR,7R,7aR)-2-{[2-(3-diethylaminopropoxy)phenyl]acetyl}-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride are obtained, after purification by chromatography on asilica gel column, in the form of a white solid.

Infrared spectrum (KBr, characterisic bands, cm⁻¹): 3090, 3060, 3030,2950, 2885, 2800, 2200, 1640, 1600, 1498, 1455, 1250, 1050, 750, 700.Proton NMR spectrum (250 MHz, DMSO-d₆ +CD₃ COOD, at room temperature, amixture of the two rotamers is observed): 1 to 1.35 (mt, 1H, axial H-6);1.18 and 1.23 (2t, J=6.5, 6H in total, -CH₂ CH₃); 1.8 to 2.2 (mt, 3H,H-6' and CH₂ --CH₂ --CH₂); 2.26 (broad d, J=13.5, 1H, equatorial H in5); 2.4 to 4 (mt, 6H, CH₂ in 1, CH₂ in 3, H-3a and H-7a); 2.8 (td,J=13.5 and 3, 1H, axial H-5); 3 to 3.2 (mt, 6H, CH₂ --N(CH₂ CH.sub.3)₂); 3.3 and 3.53 (2s, 2H, =NCOCH₂ Ar); 3.9 to 4.1 (mt, 2H, OCH₂); 4.76and 4.81 (broad 2d, J=50, 1H in total, =CHF); 6.7 to 7.5 (mt, 14H,aromatics).

The hydrochloride salt of [2-(3-diethylaminopropoxy)phenyl]acetic acidmay be prepared by carrying out the procedure as described in Example20, using 1.24 g of methyl [2-(3-diethylaminopropoxy)phenyl]acetate and20 cm³ of 6N hydrochloric acid. 1.26 g of the hydrochloride salt of[2-(3-diethylaminopropoxy)phenyl]acetic acid are obtained in the form ofa light chestnut-colored solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3250-2250,3100-3000, 3000-2850, 1722, 1600, 1585, 1495, 1472, 1450, 1385, 1250,760. Proton NMR spectrum (250 MHz, DMSO-d₆): 1.25 (t, J=7.5, 6H, 2×CH₂CH₃); 2.14 (mt, 2H, CH₂ --CH₂ --CH₂); 3.05 to 3.3 (mt, 6H, CH₂ --N(CH₂CH₃)₂); 3.53 (2s, 2H, CH₂ COO); 4.08 (t, J=6, 2H, OCH₂); 6.33 (mt, 2H,aromatics in 3 and 5); 7.23 (mt, 2H, aromatics in 4 and 6); 10.62 (mf,1H, --NH⁺ <); 12.2 (mf, 1H, COOH).

Methyl [2-(3-diethylaminopropoxy)phenyl]acetate may be prepared asdescribed in Example 20, using 1.8 g of methyl2-(3-bromopropoxy)phenylacetate and 0.66 cm³ of diethylamine. 1.24 g ofmethyl [2-(3-diethylaminopropoxy)phenyl]acetate are obtained, afterpurification by chromatography on a silica gel column, in the form of anorange-colored oil which crystallizes at room temperature.

Infrared spectrum (CCl₄, characteristic bands, cm⁻¹): 3070, 3030, 2970,2930, 2875, 2800, 1740, 1605, 1590, 1495, 1475, 1455, 1435, 1250. ProtonNMR spectrum (250 MHz, CDCl₃): 1.10 (t, J=7.5, 6H, 2×CH₂ CH₃); 1.96 (mt,2H, CH₂ --CH₂ --CH₂); 2.62 (q, J=7, 4H, N(CH₂ CH₃); 2.68 (t, J=7, 2H,CH₂ --NEt₂); 3.64 (2s, 2H, CH₂ COO); 3.7 (s, 3H, COOCH₃); 4.03 (t, J=6,2H, OCH₂); 6.9 (mt, 2H, aromatics in 3 and 5); 7.22 (mt, 2H, aromaticsin 4 and 6).

EXAMPLE 18

By carrying out the procedure as in Example 2, but using 1.37 g of{3-[N-(2-hydroxyethyl)-N-methylamino]-2-propoxy}phenylacetic acid and1.2 g of (3aR, 7R, 7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride, 0.86 g of(3aR,7R,7aR)-2-{{3-[N-(2-hydroxyethyl)-N-methylamino]-2-propoxy}phenylacetyl}-4,4-diphenyl-7-fluoroperhydroisoindoleis obtained, after purification by chromatography on a silica gelcolumn, in the form of a white meringue.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3425, 3105, 3090,3060, 3030, 2950, 2885, 2850, 2800, 1640, 1600, 1495, 1455, 1445, 1250,1050, 755, 700. Proton NMR spectrum (400 MHz, DMSO-d₆ +CD₃ COOD-d₄, at303° K. ): (at this temperature, a mixture of rotamers is observed);1.14 (broad dt, J=46 and 13.5, 1H, axial H-6); 1.85 (mt, 1H, equatorialH-6); 2.03 (mt, 2H, CH₂ --CH₂ --CH₂); 2.20 (mt, 1H, H-5); 2.3 to 3.8(mt, H-5', CH₂ --1 and CH₂ --3, H-7a and H-3a, >NCOCH₂ Ar, --CH₂--N--CH₂ CH₂ O--); 2.75 and 2.80 (2s, 3H, >N--CH₃); 3.8 to 4 (mt, 2H,ArOCH₂); 4.7 and 4.74 (2 dmt, J=50, 1H, CHF); 6.7 to 7.4 (mt, 14H,aromatics).

{3-[N-(2-Hydroxyethyl)-N-methylamino]-2-propoxy}phenylacetic acid may beprepared by carrying out the procedure as described in Example 20, using2.1 g of methyl{{3-[N-(2-hydroxyethyl)-N-methylamino]2-propoxy}phenyl}acetate and 30cm³ of 6N hydrochloric acid. 2.27 g of{3-[N-(2-hydroxyethyl)-N-methylamino]2-propoxy}phenylacetic acid areobtained in the form of a red oil.

Infrared spectrum (between cover glasses, characteristic bands, cm⁻¹):1725, 1605, 1590, 1498, 1475, 1455, 1465, 1250, 1055, 760. Proton NMRspectrum (400 MHz, DMSO-d₆, 383° K.): 1.98 (qt, J=6.5, 2H, CH₂ --C₂--CH₂); 2.84 (s, 3H, >N--CH₃); 3.15 to 3.4 (mt, 4H, NCH₂); 3.56 (s, 2H,CH₂ COO); 3.84 (t, J=6, CH₂ OH); 4.1 (t, J=6.5, ArOCH₂); 6.96 (mt, 2H,aromatics in 3 and 5); 7.24 (mt, 2H, aromatics in 4 and 6).

Methyl {{3-[N-(2-hydroxyethyl)-N-methylamino]-2-propoxy}phenyl}acetatemay be prepared as described in Example 20, using 1.8 g of methyl2-(3-bromopropoxy)phenylacetate and 0.5 cm³ of 2-(methylamino)-ethanol.0.5 g of methyl{{3-[N-(2-hydroxyethyl)-N-methylamino]-2-propoxy}phenyl}acetate isobtained, after purification by chromatography on a silica gel column,in the form of a pinkish oil.

Infrared spectrum (CH₂ Cl₂, characteristic bands, cm⁻¹): 3460, 3050,3030, 3000-2850, 2810, 1738, 1600, 1590, 1498, 1455, 1435, 1250. ProtonNMR spectrum (250 MHz, CDCl₃): 2.07 (mt, 2H, CH₂ --CH₂ --CH₂); 2.2 to2.8 (mf, 1H, OH); 2.43 (s, 3H, >N--CH₃); 2.72 (t, J=5.5, 2H, NCH₂ CH₂OH); 2.76 (t, J=7, 2H, CH₂ N); 3.64 (s, 2H, CH₂ COO); 3.71 (s, 3H, CO₂C₃); 3.71 (t, J=5.5, CH₂ OH); 4.04 (t, J=6, ArOCH₂); 6.32 (mt, 2H,aromatics in 3 and 5); 7.24 (mt, 2H, aromatics in 4 and 6).

EXAMPLE 19

By carrying out the procedure as in Example 2, but using 1.5 g of thehydrochloride salt of [2-(3-diisopropylaminopropoxy)phenyl]acetic acidand 1.3 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride, 1.57 g of(3aR,7R,7aR)-2-{[2-(3-diisopropylamino-propoxy)phenyl]acetyl}-4,4-diphenyl-7-fluoroperhydro-isoindolehydrochloride are obtained, after purification by chromatography on asilica gel column, in the form of a white solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3090, 3060, 3030,2950, 2855, 2800-2200, 1640, 1605, 1495, 1455, 1445, 1247, 755, 700.Proton NMR spectrum (250 MHz, DMSO-d₆ +CD₃ COOD, at room temperature, amixture of the two rotamers is observed ): 1 to 1.4 (mt, 1H, axial H-6); 1.2 to 1.4 (mt, 12H, isopropyl --CH₃); 1.8 to 2.2 (mt, 3H, H-6' andCH₂ --CH₂ --CH₂); 2.25 (broad d, J=13.5, 1H, equatorial H-5); 2.4 to 4(mt, H-5', CH₂ -3, CH₂ ---1, H-3a, H-7a and --N(CH(CH₃)₂)₂); 3.15 (mt,2H, --CH₂ N<); 3.3 and 3.55 (2s, 2H, >NCOCH₂ Ar); 3.9 to 4.1 (mt, 2H,OCH₂); 4.75 and 4.79 (2d, J=50, 1H, CHF); 6.7 to 7.5 (mt, 13H,aromatics).

The hydrochloride salt of [2-(3-diisopropylaminopropoxy)phenyl]aceticacid may be prepared by carrying out the procedure as described inExample 20, using 1.50 g of methyl[2-(3-diisopropylaminopropoxy)phenyl]-acetate and 30 cm³ of 6Nhydrochloric acid. 1.5 g of the hydrochloride salt of[2-(3-diisopropyl-aminopropoxy)-phenyl]acetic acid are obtained in theform of a chestnut-colored oil.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3500-2250,3100-3000, 3000-2850, 1727, 1605, 1595, 1500, 1470, 1455, 1425, 1250,760. Proton NMR spectrum (250 MHz, DMSO-d₆): 1.31 and 1.36 (2d, J=6.5,12H, isopropyl --CH₃); 2.2 (mt, 2H, CH₂ --CH₂ --CH₂); 3.21 (mt, J=7, 2H,--CH₂ N<); 3.53 (s, 2H, >NCOCH₂ Ar); 3.61 (mt, 2H, --N(CH(CH₃)₂)₂); 4.07(t, J=6, 2H, OCH₂); 6.91 (mt, 2H, aromatics in 3 and 5); 7.22 (mt, 2H,aromatics in 4 and 6); 9.98 (mf, 1H, -NH⁺ <).

Methyl [2-(3-diisopropylaminopropoxy)phenyl]acetate may be prepared asdescribed in Example 20, using 2.65 g of methyl2-(3-bromopropoxy)phenylacetate and 1.98 cm³ of diisopropylamine. 1.31 gof methyl [2-(3-diiso-propylaminopropoxy)phenyl]acetate are obtained inthe form of a yellow oil.

Infrared spectrum (CCl₄, characteristic bands, cm⁻¹): 3070, 3050, 3030,2970, 2930, 2875, 1743, 1605, 1590, 1495, 1470, 1455, 1435, 1385, 1360,1250. Proton NMR spectrum (250 MHz, DMSO-d₆): 0.97 (d, J=7, 12H,isopropyl --CH₃); 1.72 (quintuplet, J=7, 2H, CH₂ --CH₂ --CH₂); 2.55 (t,J=7, 2H, --CH₂ N<); 2.97 (mt, 2H, --N(CHMe)₂); 3.59 and 3.62 (2s, 5H,>NCOCH₂ Ar and CO₂ CH₃); 3.97 (t, J=7, 2H, OCH₂); 6.32 (mt, 2H,aromatics in 3 and 5); 7.22 (mt, 2H, aromatics in 4 and 6).

EXAMPLE 20

By carrying out the procedure as in Example 2, but using 1.45 g of thehydrochloride salt of [2-(3-piperidinopropoxy)phenyl]acetic acid and1.30 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride, 1.44 g of(3aR,7R,7aR)-2-{[2-(3-piperidinopropoxy)phenyl]acetyl}-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride are obtained, after purification by chromatography on asilica gel column, in the form of a white solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3090, 3060, 3030,2955, 2885, 2800-2200, 1640, 1605, 1498, 1455, 1445, 1250, 755, 700.Proton NMR spectrum (250 MHz, DMSO-d₆ at 433° K.): 1.27 (broad dt, J=46and 13.5, axial H-6); 1.5 to 2.1 (mf, 7H, N(CH₂ CH₂)₂ CH₂ and H-6');2.23 (mt, 2CH_(s) --CH₂ --CH₂); 2.32 (broad d, J=13.5, 1H, equatorialH-5); 2.64 (td, J=13.5 and 3, 1H, axial H-5); 2.7 to 4 (mt, CH₂ -1, CH₂-3, H-3a, H-7a and N(CH₂ CH₂)₂ CH₂); 3.13 (t, J=7.5, 2H, --CH₂ N<); 3.79(AB, 2H, NCOCH₂ Ar); 4.08 (mf, 2H, OCH₂); 4.82 (broad d, J=50, 1H, CHF);6.8 to 7.5 (mt, 14H, aromatics).

The hydrochloride salt of [2-(3-piperidinopropoxy)phenyl]acetic acid maybe prepared in the following manner:

A 6N solution of hydrochloric acid is added to 2.0 g of methyl[2-(3-piperidinopropoxy)phenyl]acetate. After refluxing for 3 hours, thesolution is concentrated to dryness at 50° C. under reduced pressure.The residue is then taken up in 30 cm³ of toluene and then the solutionis concentrated to dryness. After another treatment with toluene, 1.9 gof the hydrochloride salt of [2-(3-piperidinopropoxy)phenyl]acetic acidare obtained in the form of a white solid which is used as it is in thenext stage.

Methyl [2-(3-piperidinopropoxy)phenyl]acetate may be prepared in thefollowing manner:

1.51 g of potassium carbonate, 0.3 g of sodium iodide and then 1.0 cm³of piperidine are successively added to a solution of 2.87 g of methyl[2-(3-bromopropoxy)-phenyl]acetate in 30 cm³ of acetonitrile. Thereaction mixture is refluxed for 2 hours and then filtered. The filtrateis concentrated to dryness and the residue obtained is chromatographedon a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm,height 50 cm), eluting under a nitrogen pressure of 0.1 bar with anethyl acetate and methanol mixture (80/20 by volume) and collectingfractions of 125 cm³. Fractions 9 to 16 are pooled and concentrated todryness. The residue is triturated in diisopropyl oxide, the suspensionis filtered and the filtrate is concentrated to dryness under reducedpressure (2.7 kPa). 2.0 g of methyl[2-(3-piperidinopropoxy)phenyl]-acetate are obtained in the form of ayellow oil which is used as it in the next stage.

EXAMPLE 21

By carrying out the procedure according to that of Example [RP74066],using 1.65 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride and 1.5 g of{2-[3-(2-hydroxymethyl-(S)-1-pyrrolidinyl)propoxy]phenyl}acetic acid in160 cm³ of dry dichloromethane, 1.27 g of(3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-{{2-[3-(2-hydroxymethyl-(S)-1-pyrrolidinyl)-propoxy]phenyl}acetyl}perhydroisoindolehydrochloride are obtained in the form of a white meringue.

Proton NMR spectrum: 1.27 (broad dt, J=46 and 13.5; 1H, axial H of --CH₂-- in 6); 1.8 to 2.4 (mt, the other H of --CH₂ -- in 6 and --CH₂ --ofpyrrolidine); 2.3 (broad d, J=13.5; 1H, equatorial H of --CH₂ -- in 5);2.66 (mt, the other H of --CH₂ -- in 5); 2.4 to 4 (mt, --CH₂ -- in 1,--CH₂ -- in 3, CH in 3a, CH in 7a and CH₂ N); 3.85 (limiting ab,NCOCH₂); 4 to 4.3 (mt, 4H, --CH₂ --O); 4.84 (broad d, J=50, 1H, CHF);6.8 to 7.6 (mt, 13H, aromatics). Infrared spectrum (KBr): 3420,3105-3090-3060-3030, 2955-2885, 2800-2200, 1640, 1605-1498, 1455-1445,1250, 1065, 1050, 755-705.

2-[3-(2-Hydroxymethyl-(S)-1-pyrrolidinyl)propoxy]phenylacetic acid maybe obtained in the following manner:

A suspension of 1.65 g of methyl2-[3-(2-hydroxymethyl-(S)-1-pyrrolidinyl)propoxy]phenylacetate in 20 cm³of 6N hydrochloric acid is refluxed for 3 hours. The reaction mixture isconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is triturated in ether. 1.45 g of2-[3-(2-hydroxymethyl-(S)-1-pyrrolidinyl)propoxy]phenylacetic acid areobtained in the form of a brown oil.

Proton NMR spectrum: 1.7 to 2.3 (mt, 6H, --CH₂ -- of pyrrolidine); 3 to3.3 and 3.4 to 3.7 (2mt, 5H in total NCH₂ and NCH); 3.54 (s, 2H, CH₂COO); 3.76 (split ab, J=12.5 and 4, 2H, CH₂ O); 4.06 (mt, 2H, ArOCH₂);6.94 (mt, 2H, aromatics in ortho and para of OR); 7.22 (mt, 2H,aromatics in meta of OR); 10.35 (mt, 1H, NH^(+Cl) ⁻).

Methyl 2-[3-(2-hydroxymethyl-(S)-1-pyrrolidinyl)propoxy]phenylacetatemay be obtained in the following manner:

0.92 g of potassium carbonate, 0.22 g of sodium iodide and then 0.63 gof 2-hydroxymethyl-(S)-pyrrolidine are successively added to a solutionof 1.8 g of methyl 2-(3-bromopropoxy)phenylacetate in 20 cm³ ofacetonitrile. The reaction mixture is heated at 70° C. for 5 hours andthen, after cooling, diluted with 100 cm³ of dichloromethane, washedwith 100 cm³ of water and then with 100 cm³ of a saturated aqueoussolution of sodium chloride, dried over magnesium sulphate andconcentrated to dryness under reduced pressure (2.7 kPa). The residue ischromatographed on a Merck silica gel column (particle size 0.04-0.06mm, diameter 3 cm, height 30 cm), eluting under a nitrogen pressure of0.4 bar with an ethyl acetate and methanol mixture (90/10 by volume) andcollecting fractions of 100 cm³. Fractions 7 to 20 are pooled andconcentrated to dryness under reduced pressure (2.7 kPa). 1.55 g ofmethyl 2-[3-(2-hydroxymethyl-(S)-1-pyrrolidinyl)propoxy]-phenylacetateare obtained in the form of an oil.

Proton NMR spectrum: 1.5 to 2 (mt, 4H, CH₂ of pyrrolidine); 1.84 (mt,2H, CH₂ of the propoxy chain); 2.2 and 3.08 (2mt, 1H each, NCH₂ ofpyrrolidine); 2.4 and 2.35 (mt, 1H each, NCH₂); 2.5 (mt, 1H, NCH ofpyrrolidine); 3.22 (dd, J=11.5 and 6.5, 1H of CH₂ O); 3.44 (dd, J=11.5and 4.5, 1H, the other H of CH₂ O); 3.6 (2s, 5H, CH₂ COOCH₃); 4 (t, J=6,2H, ArOCH₂); 6.92 (mt, 2H, aromatics in ortho and para of OR); 7.22 (mt,2H, aromatics in meta of OR).

EXAMPLE 22

By carrying out the procedure as in Example 2, but using 2.3 g of thehydrochloride salt of {[3-(delta³ -1-pyrrolinyl)-2-propoxy]phenyl}aceticacid and 2.32 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride, 3.4 g of a crude product are obtained in the form of awhite meringue. This product is taken up in 100 cm³ of ethyl acetate,the solution obtained is washed with 40 cm³ of a 5% aqueous solution ofsodium bicarbonate, followed by extraction first with 30 cm³, then with20 cm³ of 1N hydrochloric acid. The acidic aqueous extracts are pooled,alkalized with 4N sodium hydroxide and then extracted again with twice50 cm³ of ethyl acetate. The organic phase is concentrated to drynessunder reduced pressure (2.7 kPa), the residue is chromatographed on aSEPHADEX LH-20 column (diameter 3 cm, height 1.4 m), eluting withmethanol and collecting fractions of 13 cm³. Fractions 35 to 38 arepooled and concentrated to dryness under reduced pressure (2.7 kPa). Theresidue is triturated in ethyl ether, the solid is drained and driedunder reduced pressure (2.7 kPa). 0.49 g of (3aR,7R,7aR)-2-{{[3-(delta³-1-pyrrolinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenyl-7-fluoroperhydroisoindolehydrochloride is obtained in the form of a white solid.

Infrared spectrum (KBr, characteristic bands, cm⁻¹): 3090, 3060, 3030,2945, 2880, 2800-2200, 1640, 1600, 1495, 1455, 1445, 1245, 755, 700.Proton NMR spectrum (200 MHz, DMSO-d₆ +CD₃ COOD at 413° K.): 1.32 (broaddt, J=46 and 13.5, 1H, axial H-6); 2.05 (mt, 1H, equatorial H-6); 2.15(qt, J=7, 2H, CH₂ --CH₂ --CH₂); 2.3 (broad d, J=13.5, 1H, equatorialH-5); 2.67 (td, J=13.5 and 3, 1H, axial H-5); 2.6 to 3.9 (mt, CH₂ -3,CH₂ -1, H-3a and H-7a); 3.35 (t, J=7, 2H, --CH₂ N<); 3.8 (limiting AB,2H, >NCOCH₂ Ar); 4.07 (s, 4H, --N(CH₂ CH)₂ ; 4.10 (t, J=7, 2H, CH₂ O);4.8 (dmt, J=50, 1H, CHF); 5.91 (s, 2H, CH═CH); 6.8 to 7.5 (mt, 14H,aromatics).

The hydrochloride salt of {[3-(delta³-1-pyrrolinyl)-2-propoxy]phenyl}acetic acid may be prepared by carryingout the procedure as described in Example 20, using 8 g of methyl{[3-(delta³ -1-pyrrolinyl)-2-propoxy]phenyl}acetate and 100 cm³ of 6Nhydrochloric acid. 4.6 g of {[3-(delta³-1-pyrrolinyl)-2-propoxy]phenyl}-acetic hydrochloride are obtained inthe form of a light beige solid; melting point 140° C.

Methyl {[3-(delta³ -1-pyrrolinyl)-2-propoxy]phenyl}acetate may beprepared as described in Example 20, using 15.6 g of methyl2-(3-bromopropoxy)phenylacetate and 3.8 g of delta³ -pyrroline. 8.0 g ofmethyl {[3-(delta³ -1-pyrrolinyl)-2-propoxy]phenyl}acetate are obtained,after purification by chromatography on a silica gel column, in the formof an orange-yellow oil.

Proton NMR spectrum (300 MHz, CDCl₃): 1.98 (mt, 2H, CH₂ --CH₂ --CH₂);2.81 (t, J=7, 2H, --CH₂ N<); 3.51 (s, 4H, --N(CH₂ CH)₂); 3.64 (s, 2H,>NCOCH₂ Ar); 3.7 (s, 3H, CO₂ CH₃); 4.06 (t, J=6.5, 2H, CH₂ O); 5.8 (s,2H, CH═CH); 6.9 (mt, 2H, aromatics in 3 and 5); 7.21 (mt, 2H, aromaticsin 4 and 6).

EXAMPLE 23

A solution of 1.32 g of(3aR,4S,7aR)-2-[(2methoxyphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindololin 100 cm³ of anhydrous dichloromethane is added over 20 minutes to asolution, cooled to 0° C., of 0.4 cm³ of 4-trifluorothiomorpholine in 20cm³ of anhydrous dichloromethane. After stirring for 2 hours at 20° C.,the reaction mixture is washed with 100 cm³ of a 5% w/v aqueous solutionof sodium bicarbonate, dried over magnesium sulphate and concentrated todryness under reduced pressure (2.7 kPa). The residue is chromatographedon a silica gel column (particle size 0.04-0.06 mm, diameter 2.5 cm,height 30 cm), eluting under a nitrogen pressure of 0.5 bar with acyclohexane and ethyl acetate mixture (50/50 by volume) and collectingfractions of 30 cm³. Fractions 10 to 20 are pooled and concentrated todryness under reduced pressure (2.7 kPa). The residue is washed withethyl ether and then with diisopropyl oxide, the solid is drained anddried. 0.38 g of(3aR,7R,7aR)-2-[(2-methoxyphenyl)-acetyl]-4,4-diphenyl-7-fluoroperhydroisoindoleis obtained in the form of a white solid; melting point 205° C.

EXAMPLE 24

A solution of 0.91 g of2-[(2-dimethylaminophenyl)-acetyl]-7,7-diphenyl-4-perhydroisoindolol, amixture of the (3aR,4S,7aR) and (3aR,4R,7aR) isomers (the 3aR,4S,7aRisomer being very predominant), obtained according to Example 17, in 30cm³ of anhydrous dichloromethane is added over 20 minutes, under anitrogen atmosphere, to a solution, cooled to 10° C., of 0.27 cm³ of4-trifluorothiomorpholine in 10 cm³ of anhydrous dichloromethane. Afterstirring for 2 hours at 20° C. the reaction mixture is successivelywashed with 25 cm³ of water and 20 cm³ of a 0.1 N aqueous solution ofsodium hydroxide, and then dried over magnesium sulphate andconcentrated to dryness under reduced pressure (2.7 kPa). The residue ischromatographed on a Merck silica gel column (particle size 0.04-0.06mm, diameter 2 cm, height 40 cm), eluting under a nitrogen pressure of0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 followed by50/50 by volume) and collecting fractions of 20 cm³. Fractions 22 to 25are pooled and concentrated to dryness under reduced pressure (2.7 kPa).The residue is washed with 10 cm³ of diisopropyl oxide, the solid isdrained and dried. 0.12 g of(3aR,7R,7aR)-2-[(2-dimethylaminophenyl)-acetyl]-4,4-diphenyl-7-fluoroperhydroisoindoleis obtained in the form of a white solid; melting point 186° C.

EXAMPLE 25

A solution of 0.15 g of sodium borohydride and 0.05 cm³ of an aqueoussolution of sodium hydroxide (at 30%) in 30 cm³ of methanol is addedover 10 minutes to a suspension, cooled to 5° C., of 3.0 g of(3aR,7aR)-2-[(2-dimethylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolonein 150 cm³ of methanol. After stirring for 2 hours at 5° C., thereaction mixture is concentrated to a reduced volume (about 30 cc) andtaken up in 150 cm³ of dichloromethane. The solution obtained is washedwith 50 cm³ of water, dried over magnesium sulphate and concentrated todryness at 50° C. under reduced pressure (2.7 kPa). The residue iscrystallized from 10 cm³ of acetonitrile, the crystals are drained,washed with acetonitrile and dried. 2.2 g of a mixture (2.2 g) of(3aR,4S,7aR)-2-[(2-dimethylaminophenyl)-acetyl]-7,7-diphenyl-4-perhydroisoindolol and(3aR,4R,7aR)-2-[(2-dimethylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolol,are obtained in the form of a white solid; melting point 156° C.

EXAMPLE 26

A solution of 0.12 g of sodium borohydride and 0.05 cm³ of 10N sodiumhydroxide in 20 cm³ of methanol is added over 10 minutes to asuspension, cooled to +5° C., of 2.0 g of(3aRS,7aRS)-7,7-diphenyl-2-phenylacetyl-4-perhydro-isoindolone in 100cm³ of methanol. The reaction mixture is stirred for 2 hours at lowtemperature, followed by the addition of 0.5 cm³ of 1N hydrochloric acidand concentration to a reduced volume, at 40° C. under reduced pressure(2.7 kPa). The residue is taken up in 50 cm^(a) of water and 150 cm³ ofdichloromethane. After stirring, the organic phase is dried overmagnesium sulphate and concentrated to dryness. The solid iscrystallized from acetonitrile, the crystals are washed withacetonitrile and diisopropyl oxide, drained and then dried. 0.24 g of(3aRS,4RS,7aRS)-7,7-diphenyl-2-phenyl-acetyl-4-perhydroisoindolol isobtained in the form of white crystals; melting point 220° C.

EXAMPLE 27

The filtrate from the crystallization of the product obtained in theexample above is concentrated to dryness. The residue is chromatographedon a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm,height 35 cm), eluting under a nitrogen pressure of 0.5 bar with a1,2-dichloroethane and methanol mixture (95/5 by volume) and collectingfractions of 50 cm³. Fractions 14 to 17 are pooled and concentrated todryness under reduced pressure (2.7 kPa). 0.28 g of(3aRS,4SR,7aRS)-7,7-diphenyl-2-phenylacetyl-4-perhydroisoindolol isobtained in the form of white crystals; melting point 222° C.

EXAMPLE 28

A solution of 0.6 g of(3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride and0.51 cm³ of triethylamine in 10 cm³ of dry dichloromethane is added to asolution of 0.41 g of ethyl (2-methoxyphenyl)-acetimidatetetrafluoroborate in 10 cm³ of dry dichloromethane. The reaction mixtureis refluxed for 3 hours. It is then treated, after re-equilibrating toroom temperature, with 5 cm³ of a 10% aqueous solution of potassiumcarbonate; the organic phase is washed with 10 cm³ of distilled water,dried over magnesium sulphate and concentrated to dryness under reducedpressure (2.7 kPa). The residue is chromatographed on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm),eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate,acetic acid and water mixture (15/1/1 by volume) and collectingfractions of 25 cm³. Fractions 24 to 38 are pooled and concentrated todryness under reduced pressure (2.7 kPa). The residue is taken up in 40cm³ of dichloromethane, washed with 10 cm³ of a saturated aqueoussolution of potassium carbonate and then with 10 cm³ of a saturatedaqueous solution of sodium chloride. The organic phase is dried overmagnesium sulphate and concentrated to dryness under reduced pressure(2.7 kPa). The residue is crystallized from isopropyl oxide. Thecrystals are drained and dried. 0.18 g of(3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[1-imino-2-(2-methoxyphenyl)ethyl]perhydroisoindoleis obtained in the form of white crystals, melting point 184° C., withdecomposition.

EXAMPLE 29

A solution of 1.56 g of ethyl (2-methoxyphenyl)-acetimidatetetrafluoroborate and 0.96 cm³ of triethylamine in 20 cm³ of drydichloromethane is added to a solution of 2 g of(3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol in 30 cm³ of drydichloromethane, and the reaction mixture is then refluxed for 2 hours.10 cm³ of a 10% aqueous solution of potassium carbonate are then added,the mixture is decanted and then the organic phase is washed with 20 cm³of water, dried over magnesium sulphate, filtered and concentrated todryness under reduced pressure (2.7 kPa). The residue is chromatographedon an alumina column (diameter 3.6 cm, height 31 cm), eluting under anitrogen pressure of 0.1 bar with a dichloromethane and methanol mixture(95/5 by volume) and collecting fractions of 50 cm³. Fractions 5 to 30are pooled and concentrated to dryness under reduced pressure (2.7 kPa).The solid obtained is washed with isopropyl oxide, drained and dried.1.4 g of(3aR,4S,7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl]-4-perhydroisoindololare obtained in the form of white crystals; melting point 105° C., withdecomposition.

The present invention also relates to pharmaceutical compositionsconsisting of a product of general formula (I) or a salt, when theseexist, optionally in combination with any other pharmaceuticallycompatible product, which may be inert or physiologically active. Thecompositions according to the invention may be used parenterally,orally, rectally or topically.

The sterile compositions for parenteral administration which may be usedin particular in the form of perfusions are preferably aqueous ornonaqueous solutions, suspensions or emulsions. Water, propylene glycol,polyethylene glycol, vegetable oils, in particular olive oil, organicesters for injections, for example ethyl oleate or other suitableorganic solvents may be used as solvent or vehicle. These compositionsmay also contain adjuvants, in particular wetting, isotonizing,emulsifying, dispersing and stabilizing agents. Sterilization may beperformed in a number of ways, for example by asepticizing filtration,by incorporating sterilizing agents into the composition, by irradiationor by heating. They may also be prepared in the form of sterile solidcompositions which may be dissolved at the time of use in a sterilemedium for injection.

The compositions for rectal administration are suppositories or rectalcapsules which contain, in addition to the active product, excipientssuch as cacao butter, semisynthetic glycerides or polyethylene glycols.

Tablets, pills, powders or granules may be used as solid compositionsfor oral administration. In these compositions, the active productaccording to the invention (optionally combined with anotherpharmaceutically compatible product) is mixed with one or more inertdiluents or adjuvants such as sucrose, lactose or starch. Thesecompositions may also comprise substances other than diluents, forexample a lubricant such as magnesium stearate.

Emulsions which are pharmaceutically acceptable, solutions, suspensions,syrups and elixirs containing inert diluents such as water or paraffinoil may be used as liquid compositions for oral administration. Thesecompositions may also comprise substances other than diluents, forexample wetting, sweetening or flavoring products.

The compositions for topical administration may be for example creams,pomades or lotions.

In human therapy, the products according to the invention may beparticularly useful in the treatment of pain of traumatic,post-surgical, menstrual, or cephalic origin, in the treatments ofanxiety, psychoses, Parkinson's disease, schizophrenia and Alzeimer'sdisease, in muscle-relaxant treatment, in the treatment of spasmodic,painful and inflammatory manifestations of the digestive tracts(ulcerative colitis, irritable colon syndrome, Crohn's disease), of theurinary tracts (cystitis) and of the respiratory tracts (asthma,rhinitis) or in gynaecology and in the treatment of migraines. The newisoindole derivatives are also useful in the treatment of rheumatoidarthritis and in disorders due to the perturbation of the immune system,in the treatments of dermatological inflammations such as psoriasis,herpes, urticarias, eczemas, photodermatitis and in eye or dentalinflammatory disorders.

The products according to the invention may also find an application inthe treatments of cardiovascular disorders such as hypotension, or inthe treatment of disorders associated with poor regulation of growth(dwarfism, hypotrophies resulting from chronic childrens diseases,osteoporosis, development of grafts).

The doses depend on the desired effect and on the duration of treatment.For an adult, they are generally between 0.25 and 1500 mg daily ingraded doses.

Generally, the physician will determine the dosage which he judges to bemost appropriate according to the age, the weight and all the otherfactors specific to the individual to be treated.

The following examples, given with no limitation being implied,illustrate compositions according to the invention.

Example A

Tablets of active product having the following composition are preparedaccording to the usual technique:

    ______________________________________                                        (3aR,7R,7aR)-2-{{[3-(1-Pyrrolidinyl)-                                                                 25 mg                                                 2-propoxy]phenyl}acetyl}-4,4-diphenyl-                                        7-fluoro-4-perhydroisoindole                                                  Starch                  83 mg                                                 Silica                  30 mg                                                 Magnesium stearate       3 mg                                                 ______________________________________                                    

Example B

Tablets of active product having the following composition are preparedaccording to the usual technique:

    ______________________________________                                        (3aR,7R,7aR)-4,4-Diphenyl-7-fluoro-                                                                  25 mg                                                  2-[(S)-2-(2-methoxyphenyl)propionyl]-                                         perhydroisoindole                                                             Starch                 83 mg                                                  Silica                 30 mg                                                  Magnesium stearate      3 mg                                                  ______________________________________                                    

We claim:
 1. Perhydroisoindole derivatives of formula: ##STR16## in which the R radicals are identical and represent hydrogen atoms or together form a bond,the symbols R' are identical and they represent phenyl radicals which are optionally substituted in position 2 or 3 by a halogen atom or by a methyl radical, the symbol X represents an oxygen atom or an NH radical, the symbol R₁ represents a phenyl radical which is optionally substituted by one halogen atom or hydroxyl or alkyl radical which may be optionally substituted by halogen atoms, amino, alkylamino or dialkylamino radicals, an alkoxy or alkylthio radical which may be optionally substituted by a hydroxyl, amino, alkylamino or dialkylamino radical which in turn is optionally substituted by a phenyl, hydroxyl or amino radicals, or by dialkylamino radicals whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle with 5 to 6 members which may contain another heteroatom chosen from oxygen, sulphur or nitrogen, optionally substituted by an alkyl, hydroxyl or hydroxyalkyl radical, or which is substituted by an amino, alkylamino or dialkylamino radical whose alkyl parts may form with the nitrogen atom to which they are attached, a heterocycle as defined above; or R₁ represents a cyclohexadienyl, naphthyl or a saturated or unsaturated, mono- or polycyclic heterocyclic radical containing 5 to 9 carbon atoms and at least one heteroatom chosen from oxygen, nitrogen or sulphur, the symbol R₂ represents a hydrogen or halogen atom or a hydroxyl, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, alkylthio, acyloxy, carboxyl, alkoxycarbonyl, dialkylaminoalkoxycarbonyl, benzyloxycarbonyl, amino, acylamino or alkoxycarbonylamino radical, the symbol R₃ represents a halogen atom or a hydroxyl radical, and the symbol R₄ represents a hydrogen atom or a halogen atom, the alkyl and acyl radicals being linear or branched and containing 1 to 4 carbon atoms, in its stereoisomeric forms or mixture thereof, as well as its salts when these exist.
 2. A perhydroisoindole derivative according to claim 1, whereinthe radicals R are hydrogen atoms, the symbols R' are phenyl radicals, the symbol X represents an oxygen atom or an NH radical, the symbol R₁ represents a phenyl radical which is optionally substituted by an alkoxy radical which may be optionally substituted by a dialkylamino radical or a dialkylamino radical whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle with 5 to 6 members, or the alkoxy is substituted by a dialkylamino radical whose alkyl parts may form with the nitrogen atom to which they are attached, a heterocycle with 5 to 6 members, the symbol R₂ represents a hydrogen atom or an alkyl radical, the symbol R₃ represents a fluorine or chlorine atom or a hydroxyl radical, and the symbol R₄ represents a hydrogen atom or, together with R₃, represents a fluorine atom, the abovementioned alkyl radicals being linear or branched and containing 1 to 4 carbon atoms, in its stereoisomeric forms or mixtures thereof, as well as its salts when these exist.
 3. 2-{{[3-(1-Pyrrolidinyl)-2-propoxyl]phenyl}acetyl}-4,4-diphenyl-7-fluoroperhydroisoindole in its stereoisomeric forms or mixtures thereof, as well as its salts.
 4. 4,4-Diphenyl-7-fluoro-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindole in its stereoisomeric forms or mixtures thereof.
 5. 2-}[2-(3-Dimethylaminopropoxy)phenyl]acetyl}-4,4-diphenyl-7-fluoroperhydroisoindole in its stereoisomeric forms or mixtures thereof, as well as its salts.
 6. 7,7-Diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolol in its stereoisomeric forms or mixtures thereof.
 7. 2-[(2-Methoxyphenyl)acetyl]-4,4-diphenyl-7-fluoroperhydroisoindole in its stereoisomeric forms or mixtures thereof.
 8. Pharmaceutical composition comprising at least one product according to claim 1, in a pure state or combined with one or more compatible and pharmaceutically acceptable adjuvants or diluents.
 9. A method of antagonizing the effects of substance P comprising administering to a patient in need thereof an effective amount of a perhydroisoindole derivative as claimed in claim
 1. 